Ageing Research Reviews 65 (2021) 101200

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Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr

Review

Sarcopenia – Molecular mechanisms and open questions

Petra Wiedmer a, Tobias Jung a, José Pedro Castro a, 1, Laura C.D. Pomatto b, 2, Patrick Y. Sun b,
Kelvin J.A. Davies b, c, d, Tilman Grune a, e, f, g, h, *
a
German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
b
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, the University of Southern California, Los Angeles, CA 90089-0191, USA
c
Molecular and Computational Biology Program, Department of Biological Sciences of the Dornsife College of Letters, Arts & Sciences, the University of Southern
California, Los Angeles, CA 90089-0191, USA
d
Department of Biochemistry & Molecular Medicine, Keck School of Medicine of USC, the University of Southern California, Los Angeles, CA 90089-0191, USA
e
German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany
f
German Center for Cardiovascular Research (DZHK), Partner Site Berlin, 13347 Berlin, Germany
g
University of Potsdam, Institute of Nutritional Science, Nuthetal, Germany
h
NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Nuthetal, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: Sarcopenia represents a muscle-wasting syndrome characterized by progressive and generalized degenerative
Molecular pathways loss of skeletal muscle mass, quality, and strength occurring during normal aging. Sarcopenia patients are mainly
Proteostasis suffering from the loss in muscle strength and are faced with mobility disorders reducing their quality of life and
Proteasome
are, therefore, at higher risk for morbidity (falls, bone fracture, metabolic diseases) and mortality.
Autophagy
Mitochondria, Muscle fibre composition
Several molecular mechanisms have been described as causes for sarcopenia that refer to very different levels
of muscle physiology. These mechanisms cover e. g. function of hormones (e. g. IGF-1 and Insulin), muscle fiber
composition and neuromuscular drive, myo-satellite cell potential to differentiate and proliferate, inflammatory
pathways as well as intracellular mechanisms in the processes of proteostasis and mitochondrial function.
In this review, we describe sarcopenia as a muscle-wasting syndrome distinct from other atrophic diseases and
summarize the current view on molecular causes of sarcopenia development as well as open questions provoking
further research efforts for establishing efficient lifestyle and therapeutic interventions.

1. Introduction muscle mass, quality, and strength with normal aging (Argiles et al.,
2015; Cruz-Jentoft et al., 2010; Gallagher et al., 2000) and is often
Aging is one of the leading risk factors for physiological decline in accompanied by a progressive increase in body fat (Gallagher et al.,
organ function and overall health (Franceschi et al., 2018; Kennedy 1996). As a result, older adults are at greater risk for morbidity (falls,
et al., 2014). At the molecular level, the aging ‘phenotype’ has been bone fracture, institutionalization) and mortality (Batsis et al., 2014).
well-characterized by the presence of protein aggregates (Raynes et al., Paradoxically, sarcopenia patients are also at increased risk for devel­
2016), lipid peroxidation (Ayala et al., 2014), and DNA damage (Aunan oping metabolic syndrome (e. g. Type II Diabetes) (Umegaki, 2015).
et al., 2016). Though all organs show age-associated markers, Skeletal muscle comprises 40–50 % of mammalian tissue and is one of
post-mitotic cells are especially damage-prone, due to their inability to the most important sites for metabolic control (Sandri, 2010). Consid­
undergo cell division. As a result, many chronic diseases of the elderly ering the ever-increasing life expectancy and the growing elderly pop­
disproportionally impact post-mitotic tissue, including skeletal muscle ulation, the prevalence of sarcopenia will certainly escalate in the
and brain. upcoming decades. This provides the rationale for careful investigation
Sarcopenia is highly prevalent in the elderly population. It is char­ and dissection of the molecular causes of sarcopenia. Understanding the
acterized by progressive and generalized degenerative loss of skeletal molecular mechanisms will build the basis for developing efficient

* Corresponding author.
E-mail address: [email protected] (T. Grune).
1
Current address: Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School.
2
Current address: National Institute of General Medical Sciences, 45 Center Drive MSC 6200, Bethesda, MD 20892, USA.

https://doi.org/10.1016/j.arr.2020.101200
Received 16 April 2020; Received in revised form 18 October 2020; Accepted 20 October 2020
Available online 29 October 2020
1568-1637/© 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
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P. Wiedmer et al. Ageing Research Reviews 65 (2021) 101200

preventive and therapeutic treatment strategies. of the presence of sarcopenia. Acute sarcopenia, e. g. related to acute
Many pathways and mechanisms underlying sarcopenia have been illness or injury, is considered to last no longer than 6 months. Chronic
characterized. Much effort has focused on identifying the role of hor­ sarcopenia, mostly related to chronic and progressive conditions, is
mones, e.g. through insulin signaling (Léger et al., 2008), inflammatory considered to last longer than 6 months (Cruz-Jentoft et al., 2019). This
pathways (Schaap et al., 2006), and loss of proteostasis (Jiao and time-dependent classification implies the regular screening of in­
Demontis, 2017b) as causes for sarcopenia. However, we have a very dividuals at risk for signs and status of sarcopenia to start therapeutic
limited understanding of sarcopenia development, due to lack of countermeasures as early as possible.
appropriate animal models and the difficulty in separating “pure sar­ Age-related degradation in skeletal muscle mass is a continuous
copenia” from other age-related comorbidities. To begin addressing this process. Defining the starting age of muscle reduction, however,
gap, the present review focuses on understanding the hallmarks of sar­ appeared to be difficult. Some studies report a reduction in lean muscle
copenia as an age-related symptom or phenomenon, mainly focusing on mass by 3–8 % per decade starting at age 30 (Paddon-Jones and Ras­
sarcopenia-related changes in muscle composition and underlying mo­ mussen, 2009). Whereas, others report a broad-range, with muscle
lecular changes such as loss of proteostasis and mitochondrial decline starting at either 27, 45, or 60 years depending on the method
dysfunction as well as inflammatory pertubations. used for analyzing lean mass or muscle mass and on the study control
population (Mitchell et al., 2012). On the other extreme, reports indicate
2. Sarcopenia definition and prevalence skeletal muscle mass decline only after the age of 50 (Gallagher et al.,
2000; Janssen et al., 2000). Due to the wide range of findings, most
2.1. Differentiating sarcopenia from other muscle wasting syndromes reports assume a relatively stable lean mass until the age of 40 and a
slow but continuous loss in lean mass thereafter, which is accelerated by
Sarcopenia represents a muscle-wasting syndrome characterized by age 70 (Mitchell et al., 2012; Murton, 2015).
progressive and generalized degenerative loss of skeletal muscle mass, Dynapenia (Greek translation for poverty of strength, power, or
quality, and strength occurring during normal aging (Argiles et al., force) is the age-associated loss of muscle strength that occurs inde­
2015; Cruz-Jentoft et al., 2010; Gallagher et al., 2000). Patients expe­ pendently from changes in muscle mass or due to neurologic or muscular
rience a multitude of physically adverse effects such as mobility disor­ diseases (Clark and Manini, 2008, 2012; Mitchell et al., 2012). This
ders, increased risk of falls and fractures, impaired ability to perform definition enables teasing apart the different disease stages. Thus,
activities of daily living, disabilities, poor quality of life, loss of inde­ dynapenia, which is associated with changes in age-related muscle
pendence, and increased risk of death (Cruz-Jentoft et al., 2010). strength, is separated from sarcopenia, which exhibits also a decline in
Therefore, the European Working Group on Sarcopenia in Older People muscle strength but due to loss in muscle mass (Clark and Manini, 2008).
(EWGSOP) promoted the recognition of sarcopenia as a geriatric syn­ Studies show that the regulation of both muscle mass and muscle
drome with the definition of mainly two criteria for clinical diagnosis of strength is independent and that distinct pathways are responsible for
sarcopenia: low muscle function (characterized by low muscle strength) each symptom (Clark and Manini, 2008, 2012; Mitchell et al., 2012).
and decreased muscle mass (Cruz-Jentoft et al., 2010). In 2019, EWG­ As mentioned above, sarcopenia, besides the functional decline,
SOP updated their guidelines for sarcopenia diagnostics (EWGSOP2) represents a muscle-wasting syndrome. The difficulty is differentiating
and prioritized decreased muscle strength as the most important diag­ sarcopenia from other muscle-wasting conditions, such as cachexia,
nostic parameter, since it mainly predicts adverse outcomes of the dis­ muscle disuse atrophy, and frailty (Nicolini et al., 2013). However, the
ease (Cruz-Jentoft et al., 2019). Therefore, impaired muscle strength causes of muscle wasting and clinical presentation differ, making these
pointing towards the presence of sarcopenia might be verified by addi­ differences diagnostically useful in the clinical and research settings.
tional determination of muscle mass. Concomitantly occurring problems Sarcopenia is mainly caused by factors inherent to skeletal muscle
in muscle performance indicate already severely established sarcopenia function such as a reduction in functional motor units, decreased
(Cruz-Jentoft et al., 2019). The molecular cause and triggers of sarco­ anabolic hormone levels and protein synthesis (Argiles et al., 2015; Cade
penia are not well understood and as a result, the differentiation from and Yarasheski, 2006; Morley et al., 2014). In contrast, cachexia may
other muscle wasting syndromes is complicated. result from serious illness associated with systemic inflammatory im­
Depending on the cause, sarcopenia can be categorized into ‘pri­ pairments, e. g. cancer or organ failure, resulting in large energy im­
mary’ or ‘secondary’ sarcopenia (Bauer et al., 2019; Cruz-Jentoft et al., balances by malnutrition (e. g. anorexia) and a hypermetabolic state
2019). In ‘primary sarcopenia’ aging is considered the only cause and it (Argiles et al., 2015; Morley et al., 2014). In a progressive state, this
is therefore also called ‘age-related sarcopenia’. Whereas ‘secondary leads to strong reductions in body weight, associated with both reduced
sarcopenia’ results from the compounding occurrence of one or more lean muscle and fat mass (Argiles et al., 2015; Cruz-Jentoft et al., 2010;
other modifying conditions, such as lack of physical activity (activi­ Drescher et al., 2016). As a consequence, most cachectic patients are
ty-related sarcopenia), advanced organ failure (disease-related sarco­ also sarcopenic (secondary sarcopenia), but most sarcopenic patients
penia), or inadequate dietary intake of energy and/or protein cannot be considered cachectic (Cruz-Jentoft et al., 2010). Therefore,
(nutrition-related sarcopenia) (Bauer et al., 2019; Cruz-Jentoft et al., sarcopenia represents a feature or a consequence of cachexia wasting
2019). However, it can be difficult to differentiate between primary and syndrome (Argiles et al., 2015). Apart from different causes, both dis­
secondary sarcopenia, since causes can overlap or intertwine particu­ eases lead to a decline in muscle mass and muscle strength, suggesting
larly in aged individuals, further indicating sarcopenia is a multi-faceted these conditions may show similar drug-treatment responses (Morley
geriatric syndrome (Cruz-Jentoft et al., 2010). Recently, sarcopenia was et al., 2014).
formally recognized as a muscle disease by receiving an ICD-10-MC Different from cachexia, sarcopenia-related loss in skeletal mass is
Diagnosis Code (Cruz-Jentoft et al., 2019). For evaluating the severity not necessarily accompanied by decreased body weight. Instead, sar­
of sarcopenia in clinical settings, the EWGSOP recommends 4 steps using copenia typically shows no change in overall body weight, but the ratio
the” F-A-C-S algorithm”. The steps of this algorithm are “find” (cases), of fat to muscle increases. This so-called ‘obesity-related sarcopenia’ or
“assess” (grip strength), “confirm” (muscle quantity or quality), and ‘sarcopenic obesity’ shows alterations in muscle composition, e.g.
“severity” (check by evaluating muscle performance), which should be ‘marbling’, resulting from fat infiltration into muscle (Cruz-Jentoft et al.,
consecutively completed (Cruz-Jentoft et al., 2019). The task force of the 2010; Visser et al., 2002). In turn, fat ‘marbling’ decreases muscle
International Conference on Sarcopenia and Frailty Research (ICSFR) quality and performance (Cruz-Jentoft et al., 2010; Visser et al., 2002).
recommends a similar approach for diagnosing sarcopenia as a basis for This trend is further exacerbated with age, as fat deposition shifts away
appropriate treatment (Dent et al., 2018). Recently, a new categoriza­ from subcutaneous fat, while intramuscular and visceral fat depots in­
tion of the disease was introduced by EWGSOP according to the duration crease (Cruz-Jentoft et al., 2010). This change in muscle mass quality

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impairs muscle function and elevates the patient’s risk of mortality (e. g. with age although age specifications are not consistently reported or
bone fracture) (Cruz-Jentoft et al., 2010; Gallagher et al., 2000; Prado categorized into age groups (Cruz-Jentoft et al., 2014; Dodds et al.,
et al., 2008). 2015). Indeed, evidence in the BASE-II study showed sarcopenia prev­
These changes in fat deposition can promote metabolic complica­ alence was higher in the oldest age group (70–84 years) when EWGSOP
tions since visceral and intramuscular fat accumulation is associated criteria were applied (Spira et al., 2016). However, when only reduced
with a higher risk for cardiovascular diseases (Neeland et al., 2015), appendicular lean mass was considered, disease prevalence did not
insulin resistance, and diabetes (Heilbronn et al., 2004). In the differ between younger (60–70 years) and older subjects (>70 years).
1999–2004 National Health and Nutrition Examination Survey about 25 Sarcopenia as an age-dependent disorder is mainly investigated and
% of adults ≥ 60 years old were diagnosed with sarcopenic obesity reported in older age groups. Prevalence rates at younger ages are only
(Batsis et al., 2016 rarely reported. Kim and colleagues determined sarcopenia prevalence
Features of sarcopenic obesity are also observed in recipients of in a control group aged 40–59 years within the Korean sarcopenic
organ transplants (Schütz et al., 2012) and in cancer patients, where it obesity study only based on skeletal mass (appendicular skeletal mass
represents an adverse prognostic factor and may considerably influence (ASM)/height2 below two standard deviations) (Kim et al., 2009). Under
chemotherapy tolerance and toxicity (Anandavadivelan et al., 2016; these conditions, sarcopenia prevalence was 2.8 % in men and 2.5 % in
Carneiro et al., 2016; Prado et al., 2008; Yip et al., 2015). women. However, rates were doubeld in subjects aged 60 years and
Sarcopenia also overlaps with frailty (Cruz-Jentoft et al., 2019). above (Kim et al., 2009).
Frailty is a geriatric syndrome, while sarcopenia is a disease. Frailty is In most studies, gender was not associated with sarcopenia preva­
characterized by age-related cumulative declines across multiple organ lence (Cruz-Jentoft et al., 2014). Yet, in other studies either men (Kim
systems resulting in impaired homeostatic reserves and reduced capac­ et al., 2016) or women (Diz et al., 2016) showed higher prevalence rates.
ity of the organism to withstand stress. Therefore, frailty increases the The pathogenesis of sarcopenia is complex and several mechanisms
individual’s vulnerability to adverse health outcomes such as falls, are believed to contribute to the phenotype (Cade and Yarasheski, 2006)
hospitalization, institutionalization, and mortality (Cruz-Jentoft et al., (s. also Fig. 1). As previously discussed, differentiating sarcopenia from
2010). Most frail people are sarcopenic, and conversely, some older other muscle atrophy syndromes is difficult. Therefore, on the molecular
people with sarcopenia are also frail. As in sarcopenia, low physical level, only general muscle atrophy mechanisms are reported here, which
performance is a hallmark of frailty. However, the frailty syndrome in­ may not only be solely a consequence of sarcopenia.
cludes additional impairments, such as unintended weight loss,
exhaustion, and weakness and largely impacts cognitive status, social 3. Sarcopenia along the hallmarks of aging
involvement, and other environmental circumstances (Cruz-Jentoft
et al., 2019). Sarcopenia is an age-related disorder. Therefore, one may attempt to
describe it using the hallmarks of aging as characterized by Lopez-Otin
2.2. Prevalence of sarcopenia et al. in 2013 (Lopez-Otin et al., 2013).
The primary hallmarks of aging consider damage on the cellular
The prevalence of sarcopenia is highly dependent on the parameters level, namely genomic instability, telomere attrition, epigenetic alter­
used for clinical diagnosis which makes it a rather subjective measure. In ation and loss of proteostasis. So far, the evidence of a genetic basis as a
a meta-analysis, using EWGSOP criteria for evaluating sarcopenia cause of sarcopenia is still low, but it is emerging. As mentioned above,
prevalence only studies accounting for both muscle mass and function functional muscle strength tests are essential for clear diagnosis of sar­
were considered. The study showed sarcopenia prevalence ranging from copenia. However, a large body of studies investigating genetic in­
1 to 29 % in community-dwelling older patients living on their own fluences on sarcopenia have been performedbased on skeletal muscle
(Cruz-Jentoft et al., 2014). Prevalence rates were higher in long-term mass or lean body mass only . Additionally, investigations have been
care facilities (14–33 %), especially in male residents (68 %), while performed in knock-out animals showing characteristics of sarcopenia.
only 10 % of acute care patients in the hospital setting met the criteria In this context, age-related DNA damage especially in satellite cells and
(Cruz-Jentoft et al., 2014). In another study analyzing chronically ill their capacity for DNA repair might play a significant role in muscle
patients, prevalence rates were evaluated by muscle mass only (based on aging (Goljanek-Whysall et al., 2016). Furthermore, it was demon­
CT scans) without considering muscle function. Prevalence rates were strated that telomere attrition takes place in satellite cells (Tichy et al.,
higher, with 15–50 % in cancer patients, 30–45 % in patients with liver 2017) leading to diminished regenerative capacity (Barberi et al., 2013;
failure, and 60–70 % in critically ill patients in intensive care units Renault et al., 2002). More specifically, a loss of the circadian clock gene
(Peterson and Braunschweig, 2016). In the 1999–2004 National Health Bmal1 (Vitale et al., 2019) as well as impaired function of the antioxi­
and Nutrition Examination Survey about 23–30 % of adults ≥60 years dant enzyme peroxiredoxin 6 (Prdx6, (Pacifici et al., 2020) have been
old were diagnosed with sarcopenia based on the measurement of discussed as factors that could lead to sarcopenia or muscle atrophy.
appendicular lean mass by dual X-ray absorptiometry (Batsis et al., Telomere attrition has been considered as a possible cause of sarcopenia,
2016). This agrees with the Berlin aging study II (BASE-II) that showed however, reported results are inconclusive. Mostly, telomere length in
sarcopenia prevalence of about 24 % based on the measurement of human studies was analyzed in peripheral blood mononuclear cells,
appendicular lean mass (Spira et al., 2016). However, considering which may have little relevance or association with telomere length in
EWGSOP criteria, sarcopenia was only present in 2–4 % of the partici­ skeletal muscle cells (Lorenzi et al., 2018). Lorenzi and colleaugues re­
pants. It appeared that reduced muscle function (estimated by either ported either no association between telomere length of leukocytes and
reduced grip strength or limited mobility) was not always accompanied sarcopenia or an association of telomere length with muscle or lean
by reduced skeletal muscle mass (Spira et al., 2016). Importantly, mass, but not with muscle strength (Lorenzi et al., 2018). However, in
reduced muscle function was associated with a greater impairment of Chinese older persons longer telomers were associated with a slower
physical performance than reduced muscle mass alone. Based on this decline in grip strength (Woo et al., 2014). Furthermore, the absence of
observation, EWGSOP prioritized muscle functional measures before Prdx6 reduced telomere length in skeletal muscle of knock-out mice,
measurement of muscle mass for diagnosing sarcopenia (s. above). which was associated with increased proteolytic drive, muscle atrophy
Hence, for sarcopenia diagnosis, measures of muscle function such as and decreased muscle strength (Pacifici et al., 2020) pointing towards a
grip strength (i.e. muscle strength) and a measure of mobility (e. g. the partial role of telomere length in the development of muscle atrophy.
“Timed Up and Go Test”) are needed in addition to determining skeletal However, telomere shortening in the absence of Prdx6 might actually be
muscle mass. a consequence of the loss in myocellular antioxidant capacity and of the
It is generally suggested that the prevalence of sarcopenia increases consequent proteostatic disbalance (Pacifici et al., 2020) and, therefore,

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Fig. 1. Major characteristics of sarcopenia comprise several components from the cellular level to neuromuscular innervation and systemic effects. This complex
mixture of components might, in combination with other accompanying situations, lead to the major features of sarcopenia.

not the main cause of muscle atrophy. Epigenetic alterations in the serum levels were associated with lower handgrip strength and dimin­
development of sarcopenia seem to play a significant role. In several ished physical performance (van Nieuwpoort et al., 2018) pointing to a
studies the methylation pattern (Gensous et al., 2019; He et al., 2019) crucial role for the GH/IGF-1 axis in skeletal muscle maintainance.
and microRNA species (Brown and Goljanek-Whysall, 2015; Golja­ Mitochondrial function is also adversely affected in the aged skeletal
nek-Whysall et al., 2016) could be associated with age-related skeletal muscle leading to compromised energy supply and elevated intracellular
muscle dysfunction including sarcopenia. Interestingly, a therapeutical oxidative stress (Cade and Yarasheski, 2006; Romanello and Sandri,
potential of relevant microRNA species has been discussed for amelio­ 2015). One key element in mitochondrial physiology associated with
rating age-related loss of muscle mass and function (Goljanek-Whysall muscle atrophy is dysfunctional mitochondrial quality control usually
et al., 2016). Besides the emerging role of epigenetic alterations, loss of provided by mitophagy, the unfolded protein response, shedding of
proteostasis plays a pivotal role in the development of sarcopenia. This vesicles, proteolysis, and degradation by the ubiquitin-proteasome sys­
primary hallmark of aging skeletal muscles has been studied extensively tem (Pickles et al., 2018). These elements will be described in more
and, as we will show below, proteostatic impairments in skeletal mus­ detail below. Celluar senescence has been defined as a stable arrest of the
cles contribute significantly to the atrophic drive that is evident in sar­ cell cycle coupled to stereotypical phenotypic changes (Lopez-Otin
copenic muscles. Intracellular mechanisms of protein homeostasis are et al., 2013). However, evidence suggest that cellular senescence plays
suggested to shift towards proteolysis. This proteolytic imbalance is only a minor role in skeletal muscle (Lopez-Otin et al., 2013).
induced by intracellular protein modifications leading to enzymatic Integrative hallmarks represent the physiologic consequences of
dysfunction and increased susceptibility to oxidative stress (Cade and primary and antagonistic hallmarks of aging and finally provide the
Yarasheski, 2006) functional decline associated with aging (Lopez-Otin et al., 2013). This
So called antagonistic hallmarks of aging comprise metabolic re­ is mainly characterized by stem cell exhaustion and altered intracellular
sponses to age-related cellular damage (i.e. primary hallmarks of aging) communication. In skeletal muscle, satellite cells represent the stem cell
and includes deregulated nutrient sensing, mitochondrial dysfunction niche playing an important role for its proliferative and regenerative
and cellular senescence (Lopez-Otin et al., 2013). Deregulated nutrient capacity (Cade and Yarasheski, 2006; Domingues-Faria et al., 2015).
sensing mainly refers to impaired function of the growth hormone With age, both the number and activity of satellite cells, e.g. their pro­
(GH)/Insulin-like factor-1 (IGF-1)-axis. It represents the main anabolic liferative and regenerative capacity, are reduced further promoting
signal for muscle protein synthesis (s. Fig. 2). Serum levels of GH, IGF-1 muscle atrophy (Verdijk et al., 2014). A more in-depth discussion of this
and mechanical growth factor (MGF) are lower in older individuals with point is presented below. Intracellular communication involves endocrine,
sarcopenia compared to non-sarcopenic individuals (Bian et al., 2020). neuroendocrine, or neuronal signaling with adjacent cells as well as with
In addition, IGF-1 and MGF were independently associated with the cells in distant tissues (Lopez-Otin et al., 2013). During aging, intra­
reduction of skeletal muscle mass (Bian et al., 2020) und lower IGF-1 cellular communication is mainly influenced by inflammatory events.

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Fig. 2. Major signaling pathways influencing synthesis and breakdown of muscle proteins . (Akt: protein kinase B; ATF-2: activating transcription factor 2; FOXO:
forkhead box proteins; GCRec: glucocorticoid receptor; GSK3: glycogene synthase kinase 3; GRE: glucocorticoid responsive element; IGF-1: insulin-like growth factor
1; IL-1: Interleukin 1 ; kB-E: kB responsive element; KLF15: Krüppel-like factor 15; MAFbx: muscle atrophy F-Box; MAPK: mitogen-activated protein kinase; mTORC1:
mammalian target of rapamycin (mTOR) complex 1; MuRF 1: muscle RING-finger protein-1 ; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells;
Nrf2: Nuclear factor E2-related factor 2; p38-Pi: phosphorylated p38 mitogen-activated protein kinase; PI3K: phosphatidylinositol 3-kinase; TNF-α: tumor necrosis
factor alpha; SMAD2/3: SMAD family transcription factors 2 and 3; STAT1: Signal transducer and activator of transcription 1; UPS: ubiquitin-proteasomal system).

Low-grade inflammation is observed in a considerable percentage of the fibers, which are mainly made up of MCH2a and MHC2x, respectively
elderly (also termed ‘inflammaging’ or ‘immunosenescence’) (France­ (Cade and Yarasheski, 2006). The expression of MHC2a and MHC2x
schi and Campisi, 2014), which may further exacerbate the pathogenesis mRNA reportedly declines with advanced age and may be responsible
of muscle atrophy (Cade and Yarasheski, 2006). Additionally, reactive for the specific loss in type II muscle fibers (Cade and Yarasheski, 2006).
oxygene species (ROS), which are increasingly present in the aged or­ The loss in muscle strength associated with sarcopenia might also be
ganism due, for example, to mitochondrial dysfunction, are suggested to a consequence of the preferential atrophy of type II fibers (Cade and
promote ‘contagious aging’ from one cell to adjacent cells (Lopez-Otin Yarasheski, 2006). Also, a decrease in the size of some type II fibers has
et al., 2013). As further described below, both inflammaging and been reported, while other type II fibers were of normal size as compared
increased presence of ROS affect skeletal muscle function during aging to muscles from young individuals (Andersen, 2003). Several studies,
and contribute to atrophic changes in the muscle. however, also report a slight decrease in the amount of type I fibers
The above mentioned age-related alterations consequently result in (Andersen, 2003) and considerable phenotypic changes in these
the phenotype of sarcopenia with the main characteristics of the loss in slow-twitch fibers (e. g. a shift in adult MHC expression) in rats at higher
muscle mass and strength accompanied by changes in muscle compo­ age leading to considerable functional impairments (Carter et al., 2010).
sition and impaired neuromuscular drive. (Cade and Yarasheski, 2006). Interestingly, a detailed examination of fiber type composition of
These phenomena are mainly provided by redistribution of muscle fiber single fibers from very old subjects revealed a switch in the fiber type
subtypes, decreased capacity of myo-satellite cells to differentiate and along the length of the muscle fiber (based on ATPase staining). Close to
proliferate (especially following muscle injury), and a decrease in one-third of the fibers in the fiber pool at very old age were neither
functional motor units, all of which considerably contribute to the loss in strictly type I nor strictly type II fibers but exhibited fibers co-expressing
muscle mass and strength (Cade and Yarasheski, 2006). We will now both MHC I and IIA (Andersen, 2003). This phenomenon of mixed fibers
discuss sarcopenia-related changes in muscle composition and under­ was not observed in young muscle fibers and may partly explain the
lying molecular changes such as loss of proteostasis and mitochondrial conflicting results of the loss in muscle mass being due to either type I or
dysfunction as well as inflammatory events in further detail. type II muscle fibers. Also, in the cross-section of muscle tissue of very
old subjects there are areas with muscle fiber type clustering, while there
4. Age-related changes in skeletal muscle composition is a random distribution of type I and type II fibers in young muscle
tissue (Andersen, 2003). These phenomena may additionally contribute
A major feature of sarcopenia is a decrease in lean muscle mass, to reduced functional efficiency of skeletal muscles with increasing age.
which is the primary source of protein in the body. This decrease is Advanced age is associated with a diminished number of motor units,
mainly caused by a decline in the number of muscle fibers, especially defined as a motor neuron with its innervated muscle fibers (Cade and
type II fibers (Cade and Yarasheski, 2006; Cho et al., 2016; Domi­ Yarasheski, 2006). Axonal cell body size and the number of motor
ngues-Faria et al., 2015; Phu et al., 2015). Lean muscle comprises type I neurons decreases with age (Kawamura et al., 1977), which may
and II fibers. Type I fibers (slow-twitch) possess greater oxidative ca­ contribute to compromised neuronal activation of skeletal muscle (Kido
pacity due to their higher density of mitochondria and capillaries and et al., 2004) and thereby further promoting age-related muscle dystro­
mainly comprise the contractile protein myosin heavy chain (MHC) 1 phy. The cause of age-related motor unit loss has not been well char­
(Cade and Yarasheski, 2006). Type II fibers (fast-twitch) possess higher acterized yet. Decreased capacity for re-innervation after motor neuron
glycolytic capacity and can be subdivided into type IIA and type IIB loss was suggested to play a role (Cade and Yarasheski, 2006). A period

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of muscle unloading in old rats, leading to hindlimb muscle atrophy was between proteins and free amino acids (Fig. 2).
accompanied by a diminished capacity for muscle remodeling and for In general, aging is associated with a decreased rate of proteolysis,
regaining initial muscle strength during reloading. This was suggested to which results in the formation of toxic protein aggregates (Breusing
be partly due to neuromuscular junction instability or denervation et al., 2009; Grune et al., 2004; Hohn et al., 2017; Pomatto and Davies,
(Baehr et al., 2016). Intriguingly, lack of restoration in muscle strength 2017; Raynes et al., 2016; Sitte et al., 2000a,b). However, it was sug­
with mass reload affected inactivity and/or denervation more in tibialis gested that protein turnover in muscle is mainly determined by the
anterior muscle than in the soleus muscle and applied to both type I and declining rate of protein synthesis (rather than degradation), which may
type II muscle fibers. This suggests an age-related deficit in neuromus­ negatively impact muscle regeneration (Cade and Yarasheski, 2006).
cular transmission, which is muscle-type specific and may become Protein synthesis rate is reduced by 30 % mainly due to changes in the
further aggravated by age-related immobility. Therfore, regular exercise synthesis of mixed muscle proteins (myofibrillar, mitochondrial and
even at old age (e. g. above age 70) has the potential of slowing down sarcoplasmic) (Cade and Yarasheski, 2006). As an example, the rate of
age-related muscle dystrophy (Cho et al., 2016). MHC synthesis is reduced in middle-aged men (approximately age 55)
Satellite cells of skeletal muscles represent the stem cell niche of this and further reduced in older individuals (approximately age 77), which
tissue and are involved in muscle growth and regeneration after injury may considerably contribute to the age-associated loss in muscle
and disease (Domingues-Faria et al., 2015). When leaving their quies­ strength (Balagopal et al., 2001). Additionally, mitochondrial protein
cent state, satellite cells can proliferate, differentiate, and fuse to synthesis is decreased with age (Cade and Yarasheski, 2006) and
augment existing muscle fibers or to form new fibers. With aging, the together, with decreased MHC synthesis, contributes considerably to
number of satellite cells per myo-fiber decreases along with its regen­ decreased muscle strength in advanced age. While the total synthesis
erative capacity (Cade and Yarasheski, 2006; Domingues-Faria et al., rate of sarcoplasmic proteins is normal, individual sarcoplasmic protein
2015). In humans, this decrease was specifically observed for satellite synthesis decreases with age. Protein turnover rates of calcium regula­
cells associated with type II myo-fibers, which correlates with the pro­ tory proteins such as the Ca2+-ATPase transporter, and the ryanodine
nounced type II fiber loss seen in aging (Domingues-Faria et al., 2015). receptor, however, declined with age (Cade and Yarasheski, 2006).
Most likely, this is associated with a decreased proliferation and growth At the molecular level, protein synthesis and protein degradation,
rate due to several age-related phenomena such as prolonged doubling are regulated by different pathways. Protein synthesis is mainly induced
time of satellite cells, reduced responsiveness to proliferating stimuli, during normal growth (e. g. by growth factors and growth hormone) or
and a reduction in telomere length throughout the proliferation cycles by conditions such as (resistance) exercise. The main anabolic signal in
(Cade and Yarasheski, 2006; Domingues-Faria et al., 2015). The skeletal muscle is insulin-like growth factor 1 (IGF-1). IGF-1 binding to
decreased proliferative capacity of muscle stem cells with age is further its receptor, a trans-membrane tyrosine kinase receptor, on the plasma
promoted by increased expression of cell cycle inhibitors. Aged satellite membrane of myocytes causes intracellular trans-phosphorylation of the
cells constitutively produce fibroblast growth factor-2 (FGF2), even in receptor and the formation of a docking site for insulin receptor sub­
the absence of injury, leading to a disrupted stem cell quiescence and strate 1 (IRS-1). This receptor activation induces IRS-1 phosphorylation
impaired self-renewal capacity (Domingues-Faria et al., 2015). Apart activating the phosphatidylinositide 3-kinases (PI3K)/protein kinase B
from proliferation, differentiation capacity of satellite cells is also (Akt) pathway. This pathway activation leads to increased protein syn­
diminished with age (Domingues-Faria et al., 2015), and is associated thesis and muscle hypertrophy by:
with a reduced number of differentiating cells and a blunted expression
of differentiation markers such as Myf-5, MyoD, Myogenin and - Inhibition of glycogen synthase kinase-3 (GSK3),
MRF4/Myf6 (Domingues-Faria et al., 2015). Consequently, a reduced - Activation of mammalian target of rapamycin complex-1 (mTORC-
rate of satellite cell differentiation into myo-tubes and a decreased 1),
expression of the final differentiation marker, myosin, were reported in - mTORC-1-mediated phosphorylation of p70S6 kinase and IF-4E-
aged rat muscle (Domingues-Faria et al., 2015). binding protein (4EBP) inhibition (Fig. 2).
On the molecular level, the imbalanced activity of two signaling
pathways, the Notch and the Wnt signaling pathways, contribute to the In addition, PI3K/Akt activation also prevents protein degradation in
age-related decrease in muscle regenerative capacity (Domingues-Faria skeletal muscle by phosphorylating and thereby inactivating O-type fork
et al., 2015). Normally, the Notch pathway is activated following muscle head box (FOXO) transcription factor. This mechanism is crucial in cell
lesion, thereby inducing satellite cell proliferation and self-renewal. cycle regulation, apoptosis, and metabolism. Of the FOXO transcription
Inhibition of this pathway by Wnt signaling allows these cells to factors FOXO1, FOXO3a, and FOXO4 are all expressed in skeletal mus­
differentiate. During aging, however, the balance between the Notch cle. Upon phosphorylation, FOXO transcription factors are unable to
and Wnt pathways required for appropriate satellite cell proliferation translocate into the nucleus, preventing the upregulation of proteolysis-
and differentiation is impaired. Aging is associated with decreased ac­ related genes, such as the E3 ligases muscle RING-finger protein-1
tivity of Notch signaling, and conversely, hyperactivity of Wnt signaling, (MuRF-1) and muscle atrophy F-Box (MAFbx) (see below). Therefore,
blocking differentiation and promoting fibrinogenic signaling (Domi­ IGF-1 stimulates both protein synthesis and the proliferation of satellite
ngues-Faria et al., 2015). cells, while suppressing protein degradation (Philippou et al., 2007)
Age-related loss of muscle mass was reported to account for up to 42 Insulin is another anabolic hormone acting on myocytes (Tokarz
% of muscle mass between the ages of 30 and 80 years with a rapid et al., 2018). Aging is characterized by decreased sensitivity of myocytes
decline after 50 years of age (Cade and Yarasheski, 2006). This implies to insulin, which may additionally contribute to diminished muscle
that relevant interventions to remediate and prevent age-related muscle mass. The decreased sensitivity to insulin found in elderly individuals
atrophy, especially exercising and diet modification, should start much may be due to increased ectopic lipid storage (e. g. of ceramides) in
earlier than age 50 when the most dramatic decline occurs. muscle (Slawik and Vidal-Puig, 2007; Tardif et al., 2014), accompanied
by impaired mitochondrial activity and muscle protein synthesis (Tardif
5. Age-related changes of molecular function in skeletal muscle et al., 2014). Additionally, reduced endothelial function may contribute
to decreased insulin sensitivity, but it can be restored by
5.1. Muscle protein homeostasis co-administration of sodium nitroprusside (a vasodilator) with a
protein-rich meal (Muller et al., 2014). Other data suggest that reduced
Skeletal muscle represents the largest reservoir of amino acids in the PPAR gamma coactivator 1-alpha (PGC-1α) signaling (involved in the
body. The regulated balance between protein synthesis and breakdown regulation of mitochondrial biogenesis in skeletal muscle) results from
(proteolysis), also known as protein homeostasis, maintains a balance reduced insulin sensitivity and decreased Akt- and mTOR-expression.

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P. Wiedmer et al. Ageing Research Reviews 65 (2021) 101200

Together, this highlights the importance of anabolic function in the myostatin gene, a small secreted protein derived from skeletal muscle
pathology of sarcopenia. and a central negative regulator of muscle growth (Braun and Marks,
Protein degradation in skeletal muscle is induced by various hor­ 2015; Hoppeler, 2016). Myostatin exerts activation of protein degra­
monal and metabolic stimuli, such as glucocorticoids, oxidative stress dation through interaction with several pathways. It inhibits phos­
and inflammatory cytokines occurring during several pathogenic con­ phorylation and thereby activation of Akt leading to instability of FOXO
ditions (denervation, malnutrition, and muscle unloading, Fig. 2). phosphorylation. Dephosphorylated FOXO transcription factors, espe­
Myocytes are particularly susceptible to oxidative damage since they are cially FOXO1 and FOXO3a, show increased expression during several
post-mitotic and are, therefore, especially predisposed to accumulate forms of atrophy and are prominent activators of MuRF-1 and MAFbx
oxidatively damaged molecules (Rom and Reznick, 2016). Also, skeletal expression by binding to FOXO-responsive elements in their promoter
muscle accounts for a large share of total oxygen consumption, region (Bodine et al., 2001; Hoppeler, 2016). Interestingly, FOXO
increasing the inherent risk of elevating mitochondria-derived reactive transcription factors not only control the transcription of the E3-ligase
oxygen species (ROS), such as hydrogen peroxide (Rom and Reznick, enzymes MuRF-1 and MAFbx inducing UPS proteasomal degradation
2016). Inflammatory cytokine production and circulation are induced but also control the transcription of core components of autophago­
by oxidative stress, and aging (“inflammaging”), and during acute or somes and lysosomes such as Bnip3, which promotes the
chronic pathogenic conditions. As an example, tumor necrosis autophagy-lysosomal system (Sandri, 2010). Therefore, both degrada­
factor-alpha (TNF-α) and interleukin-1 (IL-1) and -6 (IL-6) are relevant tion systems are interacting and are carefully regulated.
inflammatory cytokines promoting protein degradation in muscle (Rom Additionally, myostatin by binding to activin type two receptors
and Reznick, 2016). Glucocorticoids are important players in stimu­ (ActRIIA/B) phosphorylates and thereby activates the transcription
lating immediate sources of cellular energy, including the initiation of factors SMAD2 and SMAD3 (Braun and Marks, 2015). Through activa­
skeletal muscle proteolysis. Therefore, glucocorticoid levels are tion of the SMAD transcription factors, myostatin down-regulates genes
increased in some pathogenic conditions, which require higher energy involved in myogenic differentiation such as MyoD, myogenin, and
supply (e. g. sepsis, cachexia, starvation, stress and insulinopenia) myf5 (Braun and Marks, 2015), thereby compromising muscle regen­
(Hoppeler, 2016). erative capacity. Also, SMAD2 and SMAD3 activation induce MuRF-1
Protein degradation is tightly regulated in coordination with and MAFbx expression. The gene expression of MuRF-1 induced by
anabolic hormones like insulin and IGF-1 and their intracellular SMAD transcription factors was observed to be especially induced in
signaling pathways. All of the stimulators of protein degradation act on cooperation with FOXO transcription factors since multiple conserved
common intracellular pathways. FOXO-responsive elements adjacent to SMAD-binding elements were
In general, intracellular protein degradation or proteolysis is medi­ identified in the MuRF-1 promoter (Bollinger et al., 2014).
ated mainly by four mechanisms: Co-expression of SMAD3 and FOXO3a increased expression of both,
MuRF-1 as well as MAFbx genes, and this transcriptional activity was
(1) the ubiquitin proteasomal system (UPS), the major regulatory higher than with FOXO expression alone (Bollinger et al., 2014). It is
mechanism of skeletal muscle atrophy, believed that myostatin causes increased muscle protein degradation
(2) the lysosomal proteolytic system with cathepsins as major lyso­ mainly by direct activation and increased activity of FOXO, through the
somal proteases, suppression of the Akt/mTOR axis (Rodriguez et al., 2014). Further­
(3) the calcium-dependent calpains, non-lysosomal proteases, that more, myostatin-mediated degradation is suggested to be facilitated by
mediate cleavage of specific substrates, the activity of the ubiquitin-proteasome and autophagy pathways
(4) the caspases, the cysteine-dependent aspartate-specific proteases (Hoppeler, 2016).
(Rom and Reznick, 2016). Myostatin is a member of the TGF-β-family and a negative regulator
of muscle growth (Sakuma et al., 2015). Ectopic overexpression of
In skeletal muscle, catabolic stimuli increase protein degradation by myostatin in rodents led to lower muscle mass (Amirouche et al., 2009;
the ubiquitin-proteasome system (UPS) and autophagy. Calpains initiate Durieux et al., 2007), and increased myostatin expression is assumed to
the breakdown of large proteins, some of them are further degraded by contribute to muscle wasting under pathologic conditions like HIV
the UPS (Pedrozo et al., 2010; Shenkman et al., 2015). Therefore, infection, sarcopenia, or muscle disuse-induced atrophy (Sakuma et al.,
myofibrillar components are mostly turned over by the UPS (loss of 2015). Genetic inhibition of myostatin production (shown in mdx mice,
contractile force), while mitochondria and some soluble proteins are a model of Duchenne Muscular Dystrophy) causes both recovery of
preferentially degraded by autophagy (loss of endurance capacity) muscle mass and muscle force production compared to wild-type mice
(Hoppeler, 2016). (Lu-Nguyen et al., 2017). Myostatin reverses the IGF-1/PI3K/AKT hy­
The degradation process is activated by two principal pathways: the pertrophy pathway by inhibition of AKT-phosphorylation thereby
p38 mitogen activated protein kinase (MAPK) pathway and the nuclear increasing FOXO1-expression and inducing atrophy-related genes
factor-kappa B (NF-κB) pathway (Fig. 2). Additionally, glucocorticoids (McFarlane et al., 2006; Sakuma et al., 2015). Following myostatin
can directly affect gene expression via binding of dimerized ligand- treatment, the ubiquitin associated proteins MuRF-1 and MAFbx were
activated glucocorticoid receptors (GR) on glucocorticoid receptor upregulated, followed by a 60 % increase in the level of
responsive elements (GRE) on target promotor regions. ubiquitin-conjugated proteins, especially prevalent in proteins of 70 kDa
MAPK p38 is responsible for activating the expression of the muscle- or smaller (McFarlane et al., 2006) thereby promoting proteolysis.
specific E3 ligases MuRF-1 and MAFbx (Rom and Reznick, 2016). Myostatin levels increased in muscle atrophy induced by muscle
Increased activity of MAPK p38β in myotubes, for example, induces unloading (Sakuma et al., 2015). On the contrary, inhibition of myo­
phosphorylation and activation of the CCAAT/enhancer-binding statin activity was able to increase muscle mass and size (Sakuma et al.,
protein-β (C/EBPβ), a transcription factor capable of binding to and 2015). However, an age-dependent increase of myostatin levels (either
activating the MAFbx promotor (Zhang and Li, 2012). as circulating protein or as mRNA residing in skeletal muscle) as a po­
Alternatively, induction of the canonical NF-κB pathway by oxida­ tential cause of sarcopenia could not be consistently proven so far
tive stress or inflammatory cytokines may lead to MuRF-1 and MAFbx (Sakuma et al., 2015). Intriguingly, it is suggested that myostatin levels
activation. In general, genes carrying kappaB elements are known to be increase with obesity (Sakuma et al., 2015) possibly as a consequence of
involved in immune function, growth regulation, inflammation, carci­ ectopic lipid storage in skeletal muscle. For example, myostatin levels
nogenesis and apoptosis (Rom and Reznick, 2016). Among those genes is were found to be increased in plasma and myotubes of extremely obese
MuRF-1, its activation representing a key step in NF-κB-induced atrophy middle-aged women, which correlated with insulin resistance and BMI
(Rom and Reznick, 2016). NF-κB also binds to kappaB elements on the (Hittel et al., 2009). The potential role of myostatin in sarcopenic

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P. Wiedmer et al. Ageing Research Reviews 65 (2021) 101200

obesity, which is also accompanied by ectopic lipid storage in skeletal (Braun and Marks, 2015). For instance, increased amounts of miR-1 lead
muscle, has not been elucidated so far. to lower amounts of heat shock protein70 (HSP70), prevent the stabi­
As stated above, glucocorticoids represent prominent catabolic lization of phosphorylated Akt (pAkt), and enable the nuclear trans­
players in skeletal muscle homeostasis. Among the genes containing a location and activation of FOXO target genes such as MURF-1 and
glucocorticoid receptor response element (GRE) is MuRF-1. While there MAFbx, which upon upregulation, promote protein degradation (Braun
is no GRE on MAFbx promotor, MAFbx expression is still increased with and Marks, 2015). On the contrary, miR-23a, miR-27a and miR-27b
glucocorticoid action indicating that indirect activation through inter­ inhibit atrophy by either directly blocking MuRF-1 and MAFbx expres­
action with other transcription factors may occur (Braun and Marks, sion (miR-23a) or by decreasing stability and half-life of myostatin
2015). Indeed, GRE have been identified in the promoter regions of the mRNA (miR-27a and miR-27b) (Braun and Marks, 2015).
transcription factors FOXO3a and Krüppel-like factor 15 (KLF15). While
the activity of the GRE on FOXO3a promotor still needs to be verified, 5.2. The role of the UPS in skeletal muscle protein turnover
GRE activation on KLF15 promotor leads to increased KLF15 expression
(Braun and Marks, 2015). KLF15 subsequently interacts with The UPS and the lysosomal proteolytic system are the most promi­
KLF15-responsive elements in MuRF-1 and MAFbx promotor regions nent executers of intracellular proteolysis (70 %–90 % of misfolded or
and induces their expression. Overexpression of both transcription fac­ damaged proteins are degraded via the UPS (Jung et al., 2009)).
tors KLF15 and ligand-activated clucocorticoid receptor resulted in ad­ The UPS is the main cellular system to mediate cytosolic protein
ditive increases in MAFbx and MuRF-1 promoter activity and expression degradation. It does so, by recognizing and removing damaged, mis­
(Braun and Marks, 2015). Furthermore, KLF15 indirectly induces folded, and dysfunctional proteins to prevent their accumulation in
MAFbx and MuRF-1 expression via stimulation of FOXO1 and FOXO3a cytotoxic aggregates. This occurs in a highly regulated manner through
expression. Therefore, FOXO transcription factors and KLF15 act coop­ the interaction with co-factors (Jung et al., 2009). A precondition for
eratively with GRE activation to induce expression of MuRF-1 and one way of UPS-mediated degradation is a polyubiquitin chain tagged to
MAFbx. It is the synergistic interplay between ligand-bound glucocor­ proteins. Polyubiquitinated substrates carrying at least 4
ticoid receptors and several transcription factors that partly activate covalently-bound ubiquitin proteins, are recognized by the 19S regu­
each other and constitute a transcription factor network regulating lator of the UPS, which subsequently unfolds the substrate in an
protein degradation in the myocyte by activating the E3 ligases MAFbx ATP-dependent manner, releases the polyubiquitin tail to be recycled,
and MuRF-1 (Braun and Marks, 2015). Intriguingly, and shuttles the target protein into the proteolytic core for degradation.
glucocorticoid-related induction of muscle atrophy is more prominent in The UPS degradation system is, therefore, a highly energy-intensive
fast-twitch skeletal muscle that in slow-twitch muscle. This is obviously process (Benaroudj et al., 2003)
due to much higher expression of GR in these muscle types, further Polyubiquitination is not a one-way road to degradation, as 100 of
explaining the muscle fibre-specific proneness to atrophy (Braun and the so-called deubiquitinating enzymes (DUBs) are reportedly involved
Marks, 2015). Glucocorticoids also induce myostatin transcription and in the fine-tuned regulation of cellular proteostasis. However, little is
myostatin stability by regulating posttranslational modifications, known regarding the role of these identified DUBs in sarcopenia. One of
thereby further pronouncing protein degradation (Hoppeler, 2016). As the rare studies revealed that the ubiquitin-specific protease 19 (USP19)
mentioned above already, expression of MuRF-1 and MAFbx is regulated deubiquitinating enzyme, that is induced in skeletal muscle under many
by direct binding of several transcription factors such as NF-κB catabolic conditions, was also involved in muscle wasting. USP19 knock-
(including p65, c-Rel, RelB, p52, p50), the CCAAT-enhancer-binding out mice lost less muscle mass than the wild-type mice responding to
proteins (or C/EBPs), and SMAD3 opening the probability of several glucocorticoids (common in systemic muscle atrophy) and denervation
transcription factor combinations acting to induce MuRF-1 and MAFbx (model of disuse atrophy) (Bedard et al., 2015). They were characterized
gene expression (Bodine and Baehr, 2014b). by more strength and less myofiber atrophy (referring to both slow type I
Growth differentiation factor 11 (GDF11) appears to be another and fast type IIb fibers). Synthesis rates of muscle protein were com­
relevant player in the induction of muscle atrophy (Hoppeler, 2016). parable between the wild-type and knock-out mice, thus pointing to a
Although it shares about 90 % homology with myostatin in the active reduced rate of proteolysis. Expression of MuRF-1 and MAFbx were
regions of the mature protein sequence, expression patterns differ. decreased in knock-out mice as well as several genes involved in auto­
Myostatin is expressed mainly in developing and adult skeletal muscle, phagy (in this case Atg4 and Bnip3). Furthermore, in patients suffering
whereas GDF11 expression is highly tissue-specific (e. g. dental and from lung or gastrointestinal cancer, the expression of USP19 correlated
neural tissues) (Nakashima et al., 1999). Myostatin (which is also called positively with the expression of MuRF-1 and MAFbx.
GDF8) and GDF11 belong to the transforming growth factor β (TGF-β)
superfamily and share similar signaling pathways; both bind activin type 5.3. The role of the E3 ubiquitin-ligases MuRF-1 and MAFbx in skeletal
II receptors and activate the intracellular mediator SMAD 2/3 pathway. muscle atrophy
Intriguingly, GDF11 expression was shown to increase with age in mice
and humans and the highest GDF11 levels coincided with muscle pa­ The activity of specific E3 ligases determines the protein substrate
thology (Egerman et al., 2015). Therefore, it seems reasonable to suggest specificity of UPS-mediated proteolysis. MuRF-1and MAFbx are E3 li­
that GDF11 may also be involved in age-dependent protein degradation gases, initially identified for their specific expression in skeletal muscle
in skeletal muscle. However, the precise function of GDF11 for and heart of atrophic rat models that underwent hindlimb suspension,
sarcopenia-related muscle loss still needs to be unraveled. immobilization, and denervation (Bodine et al., 2001; Gomes et al.,
Myostatin has been identified as a potent inducer of producing 2001; Rom and Reznick, 2016). Additionally, increased MuRF-1 and
reactive oxygen species (ROS) in myotubes (Sriram et al., 2011). MAFbx expression in muscle tissue is also observed with fasting, dia­
Increased myostatin levels (as occurring during aging) induce TNF-α betes, cancer, inflammation, metabolic stress, and glucocorticoids, all
production via stimulation of NF-κB signaling, which increases the representing conditions associated with muscle atrophy (Bodine and
generation of ROS by NAPDH oxidase. Increased ROS levels induce a Baehr, 2014a; Gomes et al., 2001; Rom and Reznick, 2016). However,
“feed-forward loop” further increasing myostatin levels via TNF-α and due to the lack of available antibodies, the dynamics of protein
NF-κB signaling. This mechanism, therefore, maintains sustained ROS expression of these genes are not known (Bodine and Baehr, 2014a), so
production in situations of elevated myostatin levels and may worsen observations reported have been based on mRNA expression levels only.
skeletal muscle maintenance under these conditions (Sriram et al., Additionally, while several studies report an increase in mRNA of both
2011). MuRF-1 and MAFbx under atrophy inducing conditions (Bodine and
Protein turnover is also regulated on the level of microRNAs (miR) Baehr, 2014b), others report no increase or even a decrease (Bowen

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P. Wiedmer et al. Ageing Research Reviews 65 (2021) 101200

et al., 2015). So the exact role of MuRF-1 and MAFbx on the protein level polyubiquitinated by MuRF-1 in vitro (Bodine and Baehr, 2014b), the
during muscle protein degradation conditions remains elusive (Fig. 3). involved pathways still have to be determined. MAFbx targets are MyoD
Overexpression of MAFbx leads to atrophy in cultured myotubes, (a myogenic differentiaton factor found in skeletal muscle) and the
while genetic knock-out of either MAFbx or MuRF-1 leads to reduced eukaryotic translation initiation factor 3 subunit f (eIF3-f), while other
atrophy in mice in response to denervation. MAFbx and MuRF-1 knock- potential targets are MHC and several sarcomeric factors like the in­
out is associated with protection against muscle loss, of as much as 56 % termediate filament proteins vimentin and desmin (Lokireddy et al.,
and 36 %, respectively (Bodine et al., 2001). Due to the specific tissue 2011, 2012). Table 1 summarizes the protein substrates of MAFbx- and
expression and the atrophy-specific induction of MAFbx and MuRF-1, MuRF-1-mediated ubiquitination proposed so far (Bodine and Baehr,
these genes are considered key markers of muscle atrophy (Bodine 2014a; Rom and Reznick, 2016).
and Baehr, 2014a). However, MuRF-1 and MAFbx expression may also
play a role in skeletal muscle remodeling. Their expression levels are
reported to be transiently induced at the onset of reloading following
disuse atrophy and following eccentric contractions (Bodine and Baehr,
2014a). Therefore, these factors might not be pure atrogenes (i.e. a set of
genes that are sensitive markers of the atrophic processes).
The identification of protein substrates targeted by MAFbx and Table 1
MuRF-1 mediated ubiquitination is still a field of high interest (Bodine Proposed protein substrates for the E3 ligases MAFbx and MuRF-1 (Bodine and
Baehr, 2014b; Witt et al., 2005).
and Baehr, 2014a; Rom and Reznick, 2016). Until now, only two major
MuRF-1 targets have been identified: proteins involved in MAFbxa MuRF-1
ATP-generation and myofibrillar proteins (Witt et al., 2005). Though a regulatory proteins: proteins involved in ATP generation
number of myofibrillar proteins that interact with MuRF-1 (nebulin, -myogenic factor MyoD1 mainly those involved in glycolysis and
titin, MLC-2, and cTNI) were determined not to be primary targets of -myogenin glycogen metabolism, e.g. mitochondrial
-eukaryotic translation initiation ATP synthase and cytoplasmic creatine
MuRF-1-mediated polyubiquitination, those proteins were still found at
factor 3-subunit F (eIF3-f) kinase.
similar amounts in both wildtype and MuRF-1-knockout mice (Witt other potential targets: Structural/myofibrillar proteinsb:
et al., 2005). Also, overexpression of MuRF-1 did not suggest myofi­ -myosin heavy chain -titin
brillar proteins to be the primary target because transgenic mice did not -vimentin -troponin1, troponin-T
-desmin -myosin heavy and light chains
exhibit muscle atrophy or decreased amounts of myofibrillar proteins
-myosin-binding protein C
compared to the wildtype (Hirner et al., 2008; Mayans and Labeit, -nebulin, nebulin-related protein,
2012). As mentioned above, some protein substrates of MuRF-1 (other -myotilin
than MAFbx) were found to be involved in ATP-generation (especially in -T-cap
glycolysis), pointing to a role of MuRF-1 in metabolic regulation (Witt a
all identified targets rely on in vitro experiments, validation in vivo still
et al., 2005). However, MuRF-1 plays a role in polyubiquitination of the required (Bodine and Baehr, 2014a).
myosin heavy chain (MHC), but not of actin or other thin filament b
interaction is likely indirect and involves other E3 ligases (Bodine and Baehr,
proteins (Cohen et al., 2009). Although myofibrillar proteins can be 2014a).

Fig. 3. Degradation of muscle fiber proteins by the ubiquitin-proteasomal system. The muscle fibers are dissolved to sarcomeric proteins, which can then be
recognized by the activated E3 ubiquitin ligases (MuRF-1 or MAFbx). Activation of E3 ubiquitin ligases takes place by binding of ubiquitin (Ub) in a step-wise process
via E1 (ubiquitin activating enzyme) and E2 (ubiquitin conjugating enzyme) with the concomitant consumption of ATP. Several molecules of ubiquitin are bound to
the substrates in a K48-poly-ubiquitin chain. This poly-ubiquitin chain then binds to the 19S regulator of the 26S/30S proteasome, where the poly-ubiquitin chain is
split-off and the substrate protein is ‘fed’ into the 20S core proteasome where it is degraded, by successive peptide bond cleavages, to short peptides and amino acids.

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P. Wiedmer et al. Ageing Research Reviews 65 (2021) 101200

5.4. Conflicting evidence for the role of MuRF-1 and MAFbx in protein (Altun et al., 2010). These differing accounts may be due to the type of
turnover muscle investigated and the assay type used (Strucksberg et al., 2010).

The relevance of the role(s) of MuRF-1 and MAFbx in the regulation 5.5. The role of the lysosomal degradation in skeletal muscle protein
of proteostasis has yet to be fully characterized. Muscle hypertrophy, for turnover
instance, is associated with both increased protein synthesis and
degradation (Baehr et al., 2014a). As mentioned above already, lysosomal proteolysis plays an impor­
The atrophy-induced induction of MAFbx and MuRF-1 expression is tant role in intracellular protein degradation complementary to UPS-
also observed in humans (Bodine and Baehr, 2014a). However, there are mediated degradation. Lysosomes are cytoplasmic organelles having a
still contradicting observations and some studies reported no increased unique internal acidic pH environment coupled with different hydro­
expression in atrophy (Rom and Reznick, 2016). This discrepancy might lases and proteases (cathepsins). This equipment enables efficient
be explained by the cause of atrophy (e. g. either immobilization, degradation of misfolded and aggregated proteins not degradable by the
denervation, or severe illness) and/or by the time point of muscle biopsy UPS (Jackson and Hewitt, 2016). Usually, lysosomes are responsible for
relative to the triggering time point for the atrophic condition. Rodent degrading soluble proteins that are long-lived and resist unfolding,
studies revealed time-dependent dynamics of MAFbx and MuRF-1 which is a prerequisite for protein degradation by the UPS (Jackson and
expression with a rapid and strong increase within the first 48 h Hewitt, 2016; Mizushima et al., 2008). Lysosomes are able to degrade
following the atrophic trigger, followed by a persistent elevation for exogenous proteins (targeted by receptor-mediated endocytosis and
7–10 days, finally followed by a gradual decrease to baseline by 14 days pinocytosis) as well as endogenous proteins and organelles (targeted by
(Bodine and Baehr, 2014a). However, a rigorous time course study in microautophagy and macroautophagy, respectively) (Ciechanover,
humans has yet to be done. 2005). Affected proteins reach the lysosome either by lysosome fusion
Another study investigating proteasomal activity and muscle hy­ with an autophagosome or by chaperone-mediated autophagy (CMA)
pertrophy after functional overload (FO) revealed a short increase in with a lysosome (Fig. 4).
MuRF-1 and MAFbx expression (after the first 24 h) that was followed by Generally, lysosomal function, macroautophagy, and CMA decrease
significant reductions of their expression (after 7 and 14 days of func­ with age, which contributes to sarcopenia (Carnio et al., 2014; Jiao and
tional overload) (Baehr et al., 2014b). FO of the plantaris muscles of Demontis, 2017a; Mizushima et al., 2008; Sakuma et al., 2015).
mice was induced by surgical removal of the entire soleus and over half Impaired function of micro- and macroautophagy leads to diminished
of the medial and lateral gastrocnemius, resulting in hyper­ clearance rate and, therefore, the accumulation of damaged cell com­
trophy/increase of mass via removal of synergistic muscles. The primary ponents and mis-folded proteins. Among those are lipofuscin, chaper­
increase was also accompanied by a significant increase in 20S and 26S ones such as Hsp27, and other polyubiquitinylated proteins such as
proteasomal activity (beta5-subunit, starting after 24 h with a peak after p62/SQSTM1 (Jiao and Demontis, 2017a) that serve as markers for
7 days). Intriguingly, proteasomal activity remained enhanced autophagic activity. These non-degraded proteins aggregate intracellu­
throughout the 14 days of functional overload, even though MuRF-1 and larly, which further impairs the generation of autophagolysosomes and
MAFbx expression had already returned to normal or decreased 3 days inhibits lysosomal activity (Mizushima et al., 2008). Concomitantly,
after FO. Expression of FOXO1 and FOXO3a increased only from 3 to 7 age-related changes in lysosomal membrane structure lead to instability
days and declined to baseline levels by 14 days after FO. FO was also and decreased levels of LAMP-2A, which contributes to low CMA ac­
accompanied by an increase in markers of ER-stress (the enzymes BiP, tivity with increasing age (Kon and Cuervo, 2010; Mizushima et al.,
PDI, and CHOP). 2008). Decreased LAMP-2A levels are suggested to be the result of
In female MAFbx knock-out mice, the muscle mass did not increase increased degradation rather than decreased synthesis (Kon and Cuervo,
after FO, while in male MAFbx knock-out mice muscle mass increased 2010). This molecular disarrangement causes a deteriorated cellular
significantly (Baehr et al., 2014). The mice showed increased protein stress response and reduced cell viability, and may lead to muscle at­
synthesis, that matched the increase in muscle mass. Enhanced expres­ rophy and loss (Jiao and Demontis, 2017a; Mizushima et al., 2008). The
sion of the endoplasmic reticulum (ER) chaperones BiP and PDI was also age-related decline of the autophagy/lysosomal system may be caused
found, both enhancing the protein-folding and quality control of the ER by decreased expression of autophagy-related genes, lower levels of
(Baehr et al., 2014). This study concludes, that the amounts of MuRF-1 autophagy core components, and sustained mTORC1 signaling, which is
and MAFbx mRNA may not always be good markers for the actual an established inhibitor of autophagy (Jiao and Demontis, 2017a).
proteasomal proteolysis as described above, since acute alcohol intoxi­ Intriguingly, in adult skeletal muscle, lysosomal protease activities
cation (Vary et al., 2008) and glucocorticoid treatment (Baehr et al., are very sparse, further aggravating the age-related decreased auto­
2011) can induce MuRF-1 and MAFbx expression, without causing a phagic activity and its consequences in aged muscle (Bechet et al.,
corresponding increase in skeletal muscle proteolysis (alcoholic intoxi­ 2005). However, autophagy in skeletal muscle is still essential for proper
cation) or increase of proteasomal activity (glucocorticoid treatment). functioning. It has been shown in a genetic mouse model of skeletal
Others have questioned the assumed role of FOXO in MuRF-1 and muscle-specific Atg7 knock-out that autophagy is important for myo­
MAFbx expression, since FOXO1 and -3a do not increase until after fiber integrity, for the appropriate interplay between muscle and nerve,
MuRF-1 and MAFbx return to baseline levels (Baehr et al., 2014). for the quality control of mitochondria, and for the preservation of
Finally, even induction of hypertrophy elevates both degradation and muscle mass (Carnio et al., 2014; Masiero et al., 2009). Muscle-specific
synthesis of muscle proteins and thus the individual roles of both Atg7 knock-out mice possessed unstable neuromuscular junctions
MuRF-1 and MAFbx have to be better understood, including exact leading to muscle denervation. Furthermore, Atg7 deficiency blocked
identifications of their substrates. removal of dysfunctional mitochondria, which induced oxidative stress
The large inconsistencies in experimental results may even suggest a through increased ROS production and protein oxidation, leading to
major role of one of the other mentioned proteolytic pathways bringing decreased muscle strength (Carnio et al., 2014). In a similar mouse
the UPS slightly out of focus. Specifically, interpretation by Bowen and model for Atg7 muscle-specific knock-out, Masiero and colleagues re­
colleagues points to the particular importance of both the calpain and ported profound muscle atrophy and age-dependent loss in force
autophagy pathways in sarcopenia. There are, however, seemingly (Masiero et al., 2009). As described before, Atg7 null muscles showed
contradictory results, with some studies indicating that proteasome ac­ considerable disarrangements in cellular quality control such as accu­
tivity declines with age (Fernando et al., 2019; Ferrington et al., 2005), mulation of abnormal mitochondria, sarcoplasmic reticulum distension,
while others reported a significant increase of proteasomal protein disorganization of sarcomeres, and formation of aberrant concentric
concentration and activity (especially 26S) in aged sarcopenic muscle membranous structures (Masiero et al., 2009). Intriguingly, autophagy

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P. Wiedmer et al. Ageing Research Reviews 65 (2021) 101200

Fig. 4. Degradation of organells and soluble proteins in muscle fibers by the autophagy-lysosomal system. There are three types of autophagy known: macro­
autophagy, microautophagy, and chaperon-mediated autophagy. The macroautophagy pathway might encapsulate organelles or proteins forming an autophago­
some. A complex protein machinery is required to form the membrane of the autophagosome and to target substrates towards the membrane that is simultaneously
being formed. By fusion of the membrane of the autophagosome with the lysosomal membrane, the substrates are exposed to the inner lysosomal proteases (called
cathepsins). Chaperone-mediated autophagy is a process where, with the help of several chaperones such as hsp70 and hsp90, substrates (here sarcomeric proteins)
are unfolded, stabilized, transported toward the lysosome, and transported via the LAMP2A protein into the lumen of the lysosome. Here the lysosomal hsp70 (Lys-
hsp70) is shown assisting the transport.

inhibition in Atg7 knockout mice induced upregulation of UPS compo­ reduced and excessive autophagy have been associated with age-related
nents such as MAFbx and MuRF-1 accompanied by a 40 % loss of sarcopenia (Jiao and Demontis, 2017a; Wohlgemuth et al., 2010). To
myofiber size (Masiero et al., 2009). This implies a compensatory in­ prevent sarcopenia, it is important to maintain autophagy flux for
crease in protein degradation by the UPS that may cause myofiber at­ organelle recycling and to prevent the accumulation of dysfunctional
rophy and muscle mass loss at old age (Jiao and Demontis, 2017a). The proteins, mitochondria, and ER membranes, as well as to block excessive
blunted lysosomal activity at advanced age, together with potentially protein breakdown (Masiero et al., 2009).
increased protein degradation by the UPS, may partly explain sarco­
penic atrophy of the skeletal muscle. 6. Mitochondrial dysfunction during muscle aging
In addition, autophagy appears to be essential for keeping muscle
satellite stem cells in their quiescent state (García-Prat et al., 2016). The During aging, several tissues exhibit mitochondrial dysfunction and
age-related decline of autophagy in satellite cells is accompanied by ROS leakage. These observations contributed to the postulation of “the
their entry into the senescent state due to loss of protein degradation and mitochondrial free radical theory of aging” (Miquel, 1998). Progression
increased oxidative stress. This results in impaired muscle regenerative of mitochondrial dysfunction over time has also been reported for
capacity due to a decline in both the number and the function of satellite muscle tissues, but it is unclear if mitochondrial dysfunction is a cause or
cells, as observed in aged mice (García-Prat et al., 2016). a consequence (Hipkiss, 2010). Nevertheless, the bioenergetic organelle
Glycogen synthase kinase 3 (GSK-3α) was suggested a significant is certainly a central player in overall muscle aging.
intracellular regulator of skeletal muscle autophagy and myocyte func­ Mitochondria are widely believed to be the main cellular source of
tion (Sakuma et al., 2015). GSK-3α null mice are characterized by ROS, especially through complex I and III electron leakage (Nakamura
considerable activation of mTORC1, associated with suppression of et al., 2009), which generates superoxide anions after incomplete
several autophagy proteins and with sarcopenia in skeletal and cardiac reduction of oxygen. During aging, the leakage is intensified and the risk
muscle (Zhou et al., 2013). Under physiologic conditions and especially for cellular damage increases. For example, due to its localization,
in young muscle, GSK-3α modulates mTORC1 activity by enhancing mitochondrial DNA (mtDNA) is one of the primary ROS targets, result­
TSC2, thereby inhibiting mTORC1 and facilitating the synthesis of ing in the generation of faulty proteins and overall dysfunction (Chocron
autophagy proteins such as Atg12, Bnip3 and LC3. In sarcopenic muscle, et al., 2019). Generally, ROS generation is elevated in dysfunctional
however, a lower GSK-3α level has less impact on TSC2 activation and mitochondria of aged muscles (Chabi et al., 2008). To understand the
therefore hyperactivates mTORC1 resulting in the inhibition of origin of this functional impairment, skeletal muscle contractile prop­
autophagy-dependent protein degradation (Sakuma et al., 2015). erties, as well as mitochondrial biogenesis and function, were examined,
Therefore, balanced constitutive autophagic activity is essential for in addition to apoptotic susceptibility in young versus senescent rats
myocyte viability and for the prevention of sarcopenia development. (Chabi et al., 2008). Muscle mass and maximal force production was
In summary, lysosomal protein degradation is an important lower in the older animal group and could be partially explained by a 30
contributor to myocyte function and muscle fiber integrity. Both % mitochondrial content decrease in fast-twitch muscle from the aged

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P. Wiedmer et al. Ageing Research Reviews 65 (2021) 101200

animals. In addition, the peroxisome proliferator-activated receptor susceptibility, and reduced mitochondrial biogenesis driven by the ac­
gamma coactivator-1 alpha (PGC-1α), an important factor for mito­ tion of PGC-1α.
chondrial biogenesis, was also found to be decreased. Furthermore,
mitochondrial ROS production during state 3 respiration was approxi­ 7. Influence of inflammation on protein degradation in skeletal
mately 1.7-fold greater in mitochondria isolated from old animals muscle
compared to young animals and was accompanied by a 1.8-fold increase
in the DNA repair enzyme 8-oxoguanine glycosylase 1 in fast-twitch Inflammation is considered to be the driving force of muscle wasting
muscle (Chabi et al., 2008). Increased mitochondrial protein modifica­ (Argiles, 2017). It may result from tumor cells releasing cytokines (e. g.
tions such as carbonylation and nitration were also seen. Mitochondrial in cancer cachexia) or from pro-oxidant conditions. In addition,
enzyme proteomic profiling has revealed that during skeletal muscle increased permeability of the gut, resulting in invasion of intestinal
aging, nitration of complex II and carbonylation of complex I, complex microbiota into the blood stream, triggering an inflammatory response
V, and isocitrate dehydrogenase occurs (Staunton et al., 2011) and may by release of lipopolysaccharides and bacterial toxins, may also be a
result in less ATP production (Mansouri et al., 2006; Yarian et al., 2005) contributing factor. This inflammatory response may contribute to
and energy balance disruption. further mucosal damage and gut permeability and increased systemic
Moreover, Demontis and colleagues have examined several studies inflammation. While inflammatory cytokines are known to induce
indicating that mitochondrial dysfunction is relevant in skeletal muscle muscle protein degradation via the NF-kB pathways (s. above), their role
during aging (Demontis et al., 2013). Studies of isolated mitochondria in age-related sarcopenia is uncertain. Since there is a chronic low-grade
from both aged mice and humans showed changes in multiple mito­ inflammation present in aged subjects (’inflammaging’) it might be
chondrial processes and phenotypes. These included shifts in mito­ reasonable to assume that low-grade inflammation may also play a role
chondrial enzyme concentrations (Staunton et al., 2011), diminished in sarcopenic muscle protein degradation (Dalle et al., 2017). However,
mitochondrial protein synthesis (Rooyackers et al., 1996), impaired the extent of the inflammatory response in sarcopenia might be much
mitochondrial permeability transition pore function (Seo et al., 2008), lower than in cachexia induced by cancer or other serious diseases. In
mitochondrial enlargement (Terman and Brunk, 2004), increased addition, recent evidence suggests that these age-dependent changes in
mtDNA mutations (Lee et al., 1997; McKenzie et al., 2002; Melov et al., immune function may result from physiologic remodeling, which may
1995; Wanagat et al., 2001), and increasedgeneration of ROS (Mansouri beneficially contribute to longevity (Fulop et al., 2017)
et al., 2006). Accordingly, protein oxidation (i.e. carbonylation) of Both TNF-α and INF-γ are known to induce the immunoproteasome,
skeletal muscle proteins increase with age and mainly affect proteins however, much less is understood about the role of the immunopro­
involved in key myocyte functions such as cellular morphology, cellular teasome or the 11S regulator in muscle atrophy (Agarwal et al., 2010).
transport, muscle contraction (e. g. myosin-7, troponin T, In patients suffering from the autosomal-recessive auto-inflammatory
myosin-binding protein C), and energy metabolism (e. g. creatine kinase JMP-syndrome, characterized by joint contractures, muscle atrophy,
M-type, glycogene phosphorylase) (Lourenco dos Santos et al., 2015). In microcytic anemia, as well as panniculitis-induced lipodystrophy, the
mice, DNA mutations are the highest in muscle compared to any other immunoproteasome was investigated. Those patients showed a muta­
tissue (Wang et al., 2001), presumably because of the high metabolic tion in the iβ5 subunit (homozygous missense mutation c.224C > T(p.
rate. Oxidative stress is also prominently detected in aged muscle Thr75Met)), causing decreased subunit activity and potentially detri­
mitochondria, at rates higher than reported in the liver, kidney or heart mental impact on MHC class I antigen processing ability causing the
(Szczesny et al., 2010). JMP-syndrome (Agarwal et al., 2010). In recent experiments using the
In other models of muscle aging, such as Drosophila melanogaster, iβ5-specific inhibitor PR-957, a unique role of the immunoproteasome in
muscle tissue seems to display more accumulation of age-related dam­ the production of cytokines and in mediating the inflammatory pro­
age compared to other tissues, such as the brain or adipose tissue (Zheng cesses was revealed. PR-957 blocked IL-23 formation by about 80 % and
et al., 2005). For example, mitochondrial and nuclear damage are both IL-6 and TNF-α formation by about 50 %, massively ameliorating
particularly important features in Drosophila muscle impairment. If inflammation in mouse models of arthritis (Muchamuel et al., 2009).
PGC-1α is overexpressed specifically in the muscle, the flies are pro­ Inflammatory cytokines and tumor-derived factors contribute to the
tected from sarcopenia and age-related metabolic complications during activation of proteolysis. TNF-α, TNF-like weak inducer of apoptosis
aging (Wenz et al., 2009). In contrast, mice with muscle-specific PGC-1α (TWEK), tumor necrosis factor receptor (TNFR), tumor necrosis factor
knock-out show exercise inability, myopathy, and glucose homeostasis receptor-associated factor (TRAF), IL-6, IFN-γ, and leukemia inhibitory
disruption (Handschin et al., 2007a, b). Together, these studies show a factor (LIF) mediate their action through two different intracellular
deep connection between muscle aging and mitochondrial loss of pathways: the NF-κB- and p38 MAP kinase pathways (Argiles, 2017),
function. both known to induce MuRF-1 and MAFbx. In rodents, inhibitors of
Mitochondria are often implicated in the apoptosis process, and a NF-κB limited limited muscle loss in tumor-bearing animals through
caspase-independent mechanism has been extensively described in inhibition of MuRF-1 upregulation (Moore-Carrasco et al., 2007). Both
skeletal muscles (Marzetti et al., 2010; Marzetti and Leeuwenburgh, pathways induce ●NO-synthase (iNOS), resulting in large amounts of
2006; Park et al., 2010; Whitman et al., 2005), suggesting that mito­ nitric oxide that can react with superoxide (O●− 2 ). They also increase
chondrial dysfunction might be the trigger for apoptosis-mediated cell inflammatory processes, in turn forming peroxynitrite (ONOO-), the
death. Chabi and colleagues also found that the basal rates of cyto­ main cause of nitrosative stress. iNOS induction and cytokine formation
chrome c and endonuclease G release in mitochondria were 3.5- to have also been shown to be suppressed by proteasomal inhibitors
7-fold higher from senescent animals when compared to young mice (Qureshi et al., 2011). In contrast, several cytokines like IL-4 and IL-10
(Chabi et al., 2008). They concluded that sarcopenia is associated with revealed an anti-cachectic effect (Argiles and Lopez-Soriano, 1999) or
increased mitochondrial apoptotic susceptibility combined with a anti-proteolytic/anti-apoptotic effects in skeletal muscles of
reduced transcriptional drive for mitochondrial synthesis. Therefore, the tumor-bearing animals (Busquets et al., 2005; Figueras et al., 2004).
muscle mass loss observed in sarcopenia might be explained by activa­ An early anti-inflammatory strategy may be an approach to reduce
tion of the apoptosis cell-death program (Hiona and Leeuwenburgh, muscle mass loss in sarcopenia. Interestingly, obesity-related inflam­
2008; Wanagat et al., 2001). Supporting this statement, Whitman and mation induces the same cytokine “secretome” that also results in a loss
colleagues reported increased apoptotic events in myocytes of older of muscle mass. Here, hypertrophic adipocytes release free fatty acids
humans as evidenced by TUNEL assay (Whitman et al., 2005). and adipo-cytokines, triggering cytokine release by macrophage acti­
In summary, age-related sarcopenia seems to be intimately linked to vation. Loss of obesity-induced muscle mass (sarcopenic obesity) is
increased ROS production, increased mitochondrial apoptotic (probably and partially) mediated by increased proteasomal

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degradation of muscle protein. This steady-state between synthesis and 9. Conclusions and open questions
degradation is massively impacted by insulin resistance (Srikanthan
et al., 2010). A plant-extract of Artemisia daracununculus L., termed as The molecular mechanisms of sarcopenia are very similar to those of
PMI5011 was able to reduce muscle loss in sarcopenic obesity, by other diseases of muscle atrophy, which can be differentiated mainly by
changing polyubiquitination patterns, inhibiting the proteasome and the disease cause. Apart from other genetically-induced atrophies or
non-proteasomal proteolysis, and decreasing MAFbx and MuRF-1 disease-related atrophies, the main risk factor for sarcopenic muscle
expression in a mouse model of obesity-related type 2 diabetes atrophy is aging. Aging-associated co-morbidities, and conditions that
(KK-Ay) (Kirk-Ballard et al., 2014). impair muscle function, make it difficult to accurately diagnose sarco­
penia and to distinguish it from other atrophic diseases. Therefore, the
8. Preventive and interventional strategies for sarcopenia concept of secondary sarcopenia was introduced as an instrument for
facilitating diagnosis. To further obviate diagnostic difficulties, EWG­
Preventing sarcopenia or delaying its development would have a SOP updated their diagnostic guidelines in 2018 and focused on the
great impact on the quality of life for elderly persons. Current strategies most relevant parameter for predicting adverse outcomes of sarcopenia:
are mainly focused on exercise, nutrition and medication. Exercise im­ decreased muscle strength (prioritized before lower muscle mass)
proves muscle mass and function in older adults (Bowen et al., 2015; (Cruz-Jentoft et al., 2019). However, careful studies with well-defined
Phu et al., 2015). It augments muscle IGF-1 expression which leads to cohorts are still needed to improve sarcopenia diagnosis
increases in muscle protein synthesis and mass in senescent muscles Many molecular pathways and players within intracellular regula­
(Cade and Yarasheski, 2006) Exercise also exerts beneficial effects by tion of muscle atrophy have been identified already. The picture is
counteracting several of the mechanisms that cause sarcopenia. For becoming very complex due to the strong interaction of anabolic protein
example, exercise can cause a reduction of inflammation, an increase in synthesis and catabolic protein degradation pathways; the balance be­
satellite cells, and reduced fat infiltration. Interestingly, the amount of tween these two being shifted towards increased protein degradation
type-II fibers increase together with the number of satellite cells in during aging promotes net loss of muscle mass.
type-II muscle fibers (Verdijk et al., 2014). Resistance exercise training It seems that in applying the hallmarks of aging to sarcopenia, the
is more effective in increasing muscle mass and strength, while endur­ most important mechanisms currently understood to be involved in its
ance exercises improves muscle performance and helps to prevent future development are loss of proteostasis, mitochondrial dysfunction and
disability (Phu et al., 2015). Structural improvements of inflammatory disturbances, which have been decribed and discussed in
exercise-induced muscle growth are based on the addition of sarcomeres more detail. However, results are limited, especially from human
in the muscle that follows the direction dictated by the contraction mode studies, and quite often subjects have not been clearly diagnosed with
(either eccentric or concentric) (Narici et al., 2016). sarcopenia using the EWGSOP guidelines (including functional tests) but
Nutritional intervention in sarcopenia focusses on increased protein only based on diminished muscle mass. Furthermore, taking muscle
content in the diet. The application of essential amino acids, especially biopsies from sarcopenic patients, which would be essential for eluci­
of leucine in the diet or as a supplement (also containing β-hydroxy dating the molecular and physiologic interrelations in humans, raises
β-methylbutyric acid (HMB)) have been reported as being beneficial serious ethical considerations. However, as the population in many
(Argiles et al., 2015) (Domingues-Faria et al., 2015). It appears that affluent countries is aging, there will surely be more patients in the
resistance training in combination with amino acid-supplemented future suffering from age-related disorders such as sarcopenia, making it
nutrition is the best candidate to attenuate age-related muscle atrophy of increased importance to society at large. Hence, there is ample and
(Argiles et al., 2015). To ideally support the exercise-induced increase in increasing demand for further elucidating the cause(s) of the disease and
protein-synthesis rates that occur after the exercise, protein intake finding appropriate therapeutic options on the basis of carefully
should be provided within 60 min of exercise (Phu et al., 2015). designed human studies.
Furthermore, n-3 polyunsaturated fatty acids, polyphenols, and vitamin Considering the available data on the mechanisms of sarcopenia
D supplementation have been reported to diminish inflammation, development it seems that further studies are urgently needed. One
improve metabolic parameters and, therefore, support skeletal muscle aspect focusses on the relevance of fat infiltration into muscle tissue
function (Domingues-Faria et al., 2015). Caloric restriction is known to during aging and sarcopenia development, respectively. It has been
induce longevity in many experimental model systems. In rats it atten­ clearly shown, that this phenomenon compromises muscle function and
uates the age-related impairment of autophagy in skeletal muscle, which increases the individual risk of mortality, for example from bone frac­
might be one of the mechanisms by which calorie restriction attenuates tures or cardiometabolic diseases like type 2 diabetes. However, the
age-related cellular damage and cell death in skeletal muscle in vivo molecular effects of intramuscular fat depots on the metabolism of
(Wohlgemuth et al., 2010). Caloric restriction may also act by lowering muscle cells in atrophic conditions have not been elucidated yet as well
insulin levels since insulin is an inhibitor of autophagy (Mizushima as have been fat cell – myofiber signaling. The expression of Perilipin 2
et al., 2008). However, considering the beneficial effect of increased (Plin-2), a protein associated with the metabolism of intracellular lipid-
amino acid content, calorie restriction should probably be used while droplets, increases with age in skeletal muscle, which is associated with
still maintaining a sufficient protein supply. In summary, the number of decreased muscle strength and thickness in patients with limited lower
studies investigating the impact of nutrition on muscle repair in the limb mobility (Conte et al., 2015, 2013). This coincides with increased
context of aging is quite small and further research is needed to provide expression of factors related to muscle atrophy, such as MuRF-1, Mafbx
effective, efficient and reasonable strategies for preventing age-related and p53 (Conte et al., 2015). Also, intramuscular lipids and their de­
muscle atrophy (Domingues-Faria et al., 2015). rivatives were reported to impair mitochondrial function and enhanced
Several molecular pathways were suggested with a potential for drug secretion of pro-inflammatory myokines might be responsible for
development for preventing or curing sarcopenia. Among those are fac­ inducing muscle dysfunction and for producing a vicious cycle that
tors for inhibiting TNFα, SHIP-2, GSK3β or proteasome activity (Cade maintains adipose tissue and skeletal muscle inflammation (Kalinkovich
and Yarasheski, 2006). In addition, pharmacologic interventions to and Livshits, 2017). Intramuscular fat-derived factors as well as mito­
activate Akt, mTOR or p70S6K have been discussed (Cade and Yara­ chondrial damage, seem to be crucial for explaining lipotoxic effects on
sheski, 2006). Only recently, also restoring normal miRNA levels as a skeletal muscle. But the underlying mechanisms still need elucidation.
potential therapeutic against muscle aging has been introduced (Brown The other unresolved aspect of molecular mechanisms in sarcopenia
and Goljanek-Whysall, 2015). However, most of these strategies still relates to the specific regulation inside the two muscle fibers, type I and
need to be tested for efficacy and lack of serious side effects. II. Why are type II fibers more affected by sarcopenia although type I
fibers should be more prone to oxidative protein damage due to their

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higher oxidative load? Are there differences in antioxidant defenses Baehr, L.M., West, D.W., Marcotte, G., Marshall, A.G., De Sousa, L.G., Baar, K., Bodine, S.
C., 2016. Age-related deficits in skeletal muscle recovery following disuse are
between these fibers? Some experiments in mice indicate that in adap­
associated with neuromuscular junction instability and ER stress, not impaired
tive non-sarcopenic conditions the fast-twitch EDL muscle reduces protein synthesis. Aging (Albany NY) 8, 127–146.
protein oxidation by an increase in antioxidant capacity (Fernando Balagopal, P., Schimke, J.C., Ades, P., Adey, D., Nair, K.S., 2001. Age effect on transcript
et al., 2019). Further studies will be required in order to demystify the levels and synthesis rate of muscle MHC and response to resistance exercise. Am. J.
Physiol. Endocrinol. Metab. 280, E203–E208.
muscle fiber-specific handling of atrophic triggers. Barberi, L., Scicchitano, B.M., De Rossi, M., Bigot, A., Duguez, S., Wielgosik, A.,
Intensifying the investigations of molecular pathways underlying Stewart, C., McPhee, J., Conte, M., Narici, M., Franceschi, C., Mouly, V., Butler-
sarcopenia development also demands further technical improvements. Browne, G., Musaro, A., 2013. Age-dependent alteration in muscle regeneration: the
critical role of tissue niche. Biogerontology 14, 273–292.
Generating antibodies for the E3-ligases MuRF-1 and MaFbx would help Batsis, J., Mackenzie, T., Barre, L., Lopez-Jimenez, F., Bartels, S., 2014. Sarcopenia,
in recognizing the real impact of these proteins in muscular degradation. sarcopenic obesity and mortality in older adults: results from the National Health
Also, when considering the alternative protein degradation route though and Nutrition Examination Survey III. Eur. J. Clin. Nutr. 68, 1001.
Batsis, J.A., Mackenzie, T.A., Jones, J.D., Lopez-Jimenez, F., Bartels, S.J., 2016.
autophagy, static measurement of autophagy proteins and genes is not Sarcopenia, Sarcopenic Obesity and Inflammation: Results From the 1999–2004
sufficient to evaluate degradation capacity. Here monitoring autophagy National Health and Nutrition Examination Survey. Clinical Nutrition 35,
flux would provide a more realistic and useful picture. However, 1472–1483. https://doi.org/10.1016/j.clnu.2016.03.028.
Bauer, J., Morley, J.E., Schols, A., Ferrucci, L., Cruz-Jentoft, A.J., Dent, E., Baracos, V.E.,
monitoring the autophagic flux in vivo is notoriously difficult. Crawford, J.A., Doehner, W., Heymsfield, S.B., Jatoi, A., Kalantar-Zadeh, K.,
Furthermore, data on the impact of nutrition, in particular, amino Lainscak, M., Landi, F., Laviano, A., Mancuso, M., Muscaritoli, M., Prado, C.M.,
acid composition of the diet, are still limited as are the effects of diet and Strasser, F., von Haehling, S., Coats, A.J.S., Anker, S.D., 2019. Sarcopenia: a time for
action. An SCWD position paper. J. Cachexia Sarcopenia Muscle 10, 956–961.
activity on the amino acid composition of blood and plasma. The same is
Bechet, D., Tassa, A., Taillandier, D., Combaret, L., Attaix, D., 2005. Lysosomal
true for brain and mental activities and the resulting neuromuscular proteolysis in skeletal muscle. Int. J. Biochem. Cell Biol. 37, 2098–2114.
effects. Bedard, N., Jammoul, S., Moore, T., Wykes, L., Hallauer, P.L., Hastings, K.E., Stretch, C.,
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the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle
development and exacerbation, we hope to gradually get closer to being wasting. FASEB J. 29, 3889–3898.
able to identify efficient lifestyle and therapeutic interventions for pre­ Benaroudj, N., Zwickl, P., Seemuller, E., Baumeister, W., Goldberg, A.L., 2003. ATP
venting age-related loss of muscle mass and function. hydrolysis by the proteasome regulatory complex PAN serves multiple functions in
protein degradation. Mol. Cell 11, 69–78.
Bian, A., Ma, Y., Zhou, X., Guo, Y., Wang, W., Zhang, Y., Wang, X., 2020. Association
Acknowledgements between sarcopenia and levels of growth hormone and insulin-like growth factor-1
in the elderly. BMC Musculoskelet. Disord. 21, 214.
Bodine, S.C., Baehr, L.M., 2014a. Skeletal muscle atrophy and the E3 ubiquitin ligases
KJAD was supported by grant # ES003598 from the National Insti­ MuRF1 and MAFbx/atrogin-1. Am. J. Physiol. Endocrinol. Metab. 307, E469–E484.
tute of Environmental Health Sciences of the US National Institutes of Bodine, S.C., Baehr, L.M., 2014b. Skeletal muscle atrophy and the E3 ubiquitin ligases
Health, and by grant # AG052374 from the National Institute on Aging MuRF1 and MAFbx/atrogin-1. Am. J. Physiol. Endocrinol. Metab. 307, E469–484.
Bodine, S.C., Latres, E., Baumhueter, S., Lai, V.K.-M., Nunez, L., Clarke, B.A.,
of the US National Institutes of Health. Poueymirou, W.T., Panaro, F.J., Na, E., Dharmarajan, K., Pan, Z.-Q., Valenzuela, D.
TG was supported by the Deutsche Forschungsgemeinschaft (DFG, M., DeChiara, T.M., Stitt, T.N., Yancopoulos, G.D., Glass, D.J., 2001. Identification of
GR1240/20-1 and GR 1240/22-1) and is member oft he FP7 EU con­ ubiquitin ligases required for skeletal muscle atrophy. Science 294, 1704–1708.
Bollinger, L.M., Witczak, C.A., Houmard, J.A., Brault, J.J., 2014. SMAD3 augments
sortium FRAILOMIC. FoxO3-induced MuRF-1 promoter activity in a DNA-binding-dependent manner. Am.
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