NEws & VIEws

EXERCISE A fundamental premise in

exercise biology is that imposing

High-intensity exercise a greater metabolic load …

will augment acute exercise

training — too much of responses

week 3 (the highest training load), there was

a good thing? a marked decrease of intrinsic mitochondrial

respiration (IMR), which coincided with a
reduction in glucose tolerance and insulin
secretion. In contrast to the impaired glucose
John A. Hawley and David J. Bishop homeostasis observed at this time, the abun-
Exercise training can induce robust changes in mitochondria that are dance of glucose transporter type 4 (GLUT4)
in whole muscle and rates of lipid oxidation
bene­ficial for a range of metabolic health outcomes. However, a recent reached their highest levels. Physical perfor-
study suggests there might be an upper limit to the amount of high- mance and maximal oxygen consumption
intensity training that can be tolerated before disruptions to mitochondrial increased throughout the study, ­regardless of
function and whole-body metabolic homeostasis occur. the training load.
To place these data in context, several
Refers to Flockhart, M. et al. Excessive exercise training causes mitochondrial functional impairment and decreases caveats need to be acknowledged. First, the
glucose tolerance in healthy volunteers. Cell Metab. [Link] (2021).
‘one-dimensional’ training model used by
Flockhart et al.7 (consisting exclusively of
Exercise poses a major challenge to cellu- unlike most medicines, there are gaps in our HIIT) does not reflect the typical approach
lar homeostasis, initiating widespread per- understanding of the optimal dose of exercise of incorporating training sessions from a
turbations in numerous tissues and organs required to improve cardiorespiratory fitness broad ‘menu’ of workouts, each with differ-
that are caused by or are a response to the and metabolic health. A fundamental premise ent goals and performed over a wide range of
increased metabolic activity of contracting in exercise biology is that imposing a greater exercise intensities6. Second, a training strat-
skeletal muscles1. To minimize these dis- metabolic load and provoking perturbations egy that impairs one attribute might promote
turbances during subsequent challenges, in cellular homeostasis will augment acute another; while IMR was reduced after ‘exces-
several training-induced metabolic and mor- exercise responses that, when repeated over sive’ training, there was an increase in mark-
phological adaptations take place1, includ- time, will amplify adapta­t ion1,6. However, ers of mitochondrial content (for example,
ing the growth and division of pre-existing when the balance between the train­ing load citrate synthase activity). Finally, short-term
mitochondria (that is, mitochondrial bio- (intensity × duration × frequen­cy) and recov- investigations can only provide a snapshot
genesis)2. More than 50 years ago, Holloszy3 ery is disturbed, symptoms of ‘over­reaching’ of the cellular and whole-body responses to
demonstrated elevated activity of several might develop, with adverse physio­logical, an intervention: the large (40%) decrease in
mitochondrial enzymes, coupled with higher psychological and func­tional out­comes. The IMR reported by Flockhart et al.7 might be
levels of respiratory control, in the skeletal recent findings of the study by Flockhart transient, and a decrease of this magnitude
muscle of exercise-trained rats compared et al.7 suggest there might be an upper limit is unlikely with continued training of this
with untrained animals. A major innovation to the amount of HIIT that can be tolerated type. Notwithstanding these limitations, the
of Holloszy’s3 exercise protocol was the use of by healthy individuals before disruptions findings provide new knowledge and prompt
high-intensity interval training (HIIT), with to mitochondrial function and whole-body several questions worthy of discussion.
the tacit assumption that any exercise sig- metabolic h ­ omeostasis occur. The first question is whether measures
nal needs to exceed a minimum ‘threshold In this study 7, healthy volunteers (six from isolated mitochondria, a technique
stimuli’ to induce metabolic adaptations in women and five men) completed 14 HIIT yielding only a small sub-population of
muscle1,2. Indeed, the training regimen pio- sessions on a cycle ergometer throughout the mitochondria that might not be repre-
neered by Holloszy3 can be viewed as the orig- a 4-week period, during which changes in sentative of the overall mitochondrial pool
inal prototype for the current wave of HIIT mitochondrial content and function, glucose within muscle, accurately reflect changes to
protocols widely accepted as a potent stimulus tolerance, whole-body metabolism and power in vivo mitochondrial function (Fig. 1). In
for physiological remodelling in humans4. output during the HIIT sessions were moni- this regard, changes to ex vivo mitochondrial
Exercise training can also help prevent and tored. During the first 3 weeks, the training function in sarcopenic muscle, measured
treat a range of chronic metabolic disorders5, load for each participant was progressively in permeabilized muscle fibres containing
leading to the widespread acceptance of the increased. In the fourth week, the load was all of their mitochondria and where normal
concept that ‘exercise is medicine’. However, reduced to allow for recovery. At the end of mitochondrial morphology and intracellular

Nature Reviews | Endocrinology volume 17 | JULY 2021 | 385

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News & Views

A second related question is whether the metabolic flexibility was preserved (that is,
the results … expose gaps decrease in IMR respiration is merely a tran- rates of whole-body fat oxidation peaked).
in our current understanding sient phenomenon. Muscle biopsy samples As in many previous investigations, there
in the study of Flockhart et al.7 were taken is often a mismatch between the changes in
of the optimal dose of exercise
14 h after the final training session, and any so-called mechanistic or cellular variables and
required to improve metabolic observed changes might reflect an acute whole-body functional outcomes6. Indeed, the
health response that ‘rebounds’ during the adaptation majority of studies to date have either taken
phase following exercise1. In support of this a mechanistic approach or focused solely
interactions are preserved, are less severe than contention, IMR recovered following 1 week on applied performance outcomes, mak-
revealed by isolated organelle procedures8. of reduced-volume training7. Furthermore, ing it hard to infer any causality6. While the
Indeed, the decrease in IMR reported by in separate studies, biopsy samples taken results of Flockhart et al.7 expose gaps in our
Flockhart et al. 7 was halved (20% versus 72 h after the last training session following current understanding of the optimal dose
40%), and no longer statistically significant, short-term, high-volume, intensified train- of exercise required to improve metabolic
when normalized to citrate synthase activity ing reveal an increase in m ­ itochondrial health and cardiorespiratory fitness, they also
measured in the isolated mitochondria sus- ­respiration in permeabilized fibres9,10. highlight the need to integrate observations
pension used for respiration measurements. A final question is whether the reduction from cells, tissue and whole-body responses
This finding suggests a large decrease in cit- in IMR after excessive training plays a caus- in a physiological context so that ultimately
rate synthase activity in the mitochondrial ative role in the observed disturbances in these findings can be translated into evidence-
isolates after 1 week of excessive training whole-body glucose control. While changes based ­recommendations for optimal exercise
in the face of an increase in citrate synthase in glucose tolerance were correlated to prescription.
activity in whole-muscle homogenates. In vol- changes in IMR at serial time points through- John A. Hawley 1 ✉ and David J. Bishop 2

unteers of similar aerobic fitness who com- out the study, the strength of the relation- 1
Exercise and Nutrition Research Program, Mary
pleted a substantially greater training load ship between these two variables (that is, MacKillop Institute for Health Research, Australian
than participants in the Flockhart et al.7 study, the explained variance) was small. Indeed, Catholic University, Melbourne, Victoria, Australia.
Granata et al.9,10 reported a 20–50% increase it is hard to reconcile the reductions in glu- 2
Institute for Health and Sport (iHeS), Victoria
in all ex vivo mitochondrial respiration states cose tolerance observed after the week of University, Melbourne, Victoria, Australia.
measured using the permeabilized muscle excessive training at a time when GLUT4 ✉e-mail: [Link]@[Link]
fibre technique. in whole muscle was most abundant, and [Link]

1. Hawley, J. A. et al. Integrative biology of exercise.

Cell 159, 738–749 (2014).
2. Perry, C. G. R. & Hawley, J. A. Molecular basis of
exercise-induced skeletal muscle mitochondrial
biogenesis: Historical advances, current knowledge,
and future challenges. Cold Spring Harb. Perspect.
Med. 8, a029686 (2018).
3. Holloszy, J. O. Biochemical adaptations in muscle.
Effects of exercise on mitochondrial oxygen uptake
respiration and respiratory enzyme activity in skeletal muscle.
In vivo J. Biol. Chem. 242, 2278–2282 (1967).
4. MacInnis, M. J. & Gibala, M. J. Physiological
adaptations to interval training and the role of
exercise intensity. J. Physiol. 595, 2915–2930
(2017).
? 5. Ruegsegger, G. N. & Booth, F. W. Health benefits
of exercise. Cold Spring Harb. Perspect. Med. 8,
a029694 (2018).
6. Hawley, J. A. et al. Maximizing cellular adaptation to
ochondria

endurance exercise in skeletal muscle. Cell Metab. 27,

962–976 (2018).
Z disc 7. Flockhart, M. et al. Excessive exercise training
causes mitochondrial functional impairment and
ed mit

decreases glucose tolerance in healthy volunteers.

Cell Metab. [Link]
Ex vi

017 (2021).
olat

8. Picard, M. et al. Mitochondrial functional impairment

vo

Permabilized muscle fibre

with aging is exaggerated in isolated mitochondria

s

m
i
in

compared to permeabilized myofibers. Aging Cell 9,

ito
ion

HIIT 1032–1046 (2010).

ch
at

Actin thin 9. Granata, C. et al. Multi-omics reveal unexpected

r nd
pi ria
complexity of mitochondrial adaptations to training
res l re filament
itro spi
ratio in human skeletal muscle. Preprint at bioRxiv
In v [Link]
n Myosin thick
filament (2021).
10. Granata, C. et al. Mitochondrial adaptations to
high-volume exercise training are rapidly reversed
after a reduction in training volume in human skeletal
muscle. FASEB J. 30, 3413–3423 (2016).

Acknowledgements
Mitochondrion Work in the authors’ laboratories is, in part, funded by an
Australian Research Council grant DP160102176, “Molecular
Fig. 1 | Methodological considerations when interpreting mitochondrial function. Caution networks underlying exercise-induced mitochondrial
biogenesis in humans”.
is warranted when interpreting data from isolated organelles, as they consist of only a fraction of
total mitochondria and lack normal mitochondrial morphology and functional interactions with Competing interests
surrounding cellular structures. HIIT, high-intensity interval training. The authors declare no competing interests.

386 | JULY 2021 | volume 17 [Link]/nrendo

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