Cancer cachexia is a complex syndrome generated by interaction between the host and tumour cells ... more Cancer cachexia is a complex syndrome generated by interaction between the host and tumour cells with a background of treatment effects and toxicity. The complexity of the physiological pathways likely involved in cancer cachexia necessitates a holistic view of the relevant biology. Emergent properties are characteristic of complex systems with the result that the end result is more than the sum of its parts. Recognition of the importance of emergent properties in biology led to the concept of systems biology wherein a holistic approach is taken to the biology at hand. Systems biology approaches will therefore play an important role in work to uncover key mechanisms with therapeutic potential in cancer cachexia. The 'omics' technologies provide a global view of biological systems. Genomics, transcriptomics, proteomics, lipidomics and metabolomics approaches all have application in the study of cancer cachexia to generate systems level models of the behaviour of this syndrome. The current work reviews recent applications of these technologies to muscle atrophy in general and cancer cachexia in particular with a view to progress towards integration of these approaches to better understand the pathology and potential treatment pathways in cancer cachexia.
Applied Physiology, Nutrition, and Metabolism, 2015
The measurement of mitochondrial protein synthesis after food ingestion, contractile activity, an... more The measurement of mitochondrial protein synthesis after food ingestion, contractile activity, and/or disease is often used to provide insight into skeletal muscle adaptations that occur in the longer term. Studies have shown that protein ingestion stimulates mitochondrial protein synthesis in human skeletal muscle. Minor differences in the stimulation of mitochondrial protein synthesis occur after a single bout of resistance or endurance exercise. There appear to be no measurable differences in mitochondrial protein synthesis between critically ill patients and aged-matched controls. However, the mitochondrial protein synthetic response is reduced at a more advanced age. In this paper, we discuss the challenges involved in the measurement of human skeletal muscle mitochondrial protein synthesis rates based on stable isotope amino acid tracer methods. Practical guidelines are discussed to improve the reliability of the measurement of mitochondrial protein synthesis rates. The value of the measurement of mitochondrial protein synthesis after a single meal or exercise bout on the prediction of the longer term skeletal muscle mass and performance outcomes in both the healthy and disease populations requires more work, but we emphasize that the measurements need to be reliable to be of any value to the field.
Obesity and aging are characterized by decreased insulin sensitivity (IS) and muscle protein synt... more Obesity and aging are characterized by decreased insulin sensitivity (IS) and muscle protein synthesis. Intramuscular ceramide accumulation has been implicated in insulin resistance during obesity. We aimed to measure IS, muscle ceramide level, protein synthesis, and activation of intracellular signaling pathways involved in translation initiation in male Wistar young (YR, 6-month) and old (OR, 25-month) rats receiving a low-(LFD) or a high-fat diet (HFD) for 10 weeks. A corresponding cellular approach using C2C12 myotubes treated with palmitate to induce intracellular ceramide deposition was taken. A decreased ability of adipose tissue to store lipids together with a reduced adipocyte diameter and a development of fibrosis were observed in OR after the HFD. Consequently, OR fed the HFD were insulin resistant, showed a strong increase in intramuscular ceramide level and a decrease in muscle protein synthesis associated with increased eIF2a phosphorylation. The accumulation of intramuscular lipids placed a lipid burden on mitochondria and created a disconnect between metabolic and regulating pathways in skeletal muscles of OR. In C2C12 cells, palmitate-induced ceramide accumulation was associated with a decreased protein synthesis together with upregulated eIF2a phosphorylation. In conclusion, a reduced ability to expand adipose tissues was found in OR, reflecting a lower lipid buffering capacity. Muscle mitochondrial activity was affected in OR conferring a reduced ability to oxidize fatty acids entering the muscle cell. Hence, OR were more prone to ectopic muscle lipid accumulation than YR, leading to decreased muscle protein anabolism. This metabolic change is a potential therapeutic target to counter sarcopenic obesity.
The increasing prevalence of obesity among elderly people has led to the definition of the concep... more The increasing prevalence of obesity among elderly people has led to the definition of the concept of sarcopenic obesity. This concept is defined as the potential to combine muscle metabolic changes associated with both aging and obesity. Several definitions have been proposed, but the absence of a consensus led to great variability in the prevalence of this phenomenon in literature.
Inflammation and ectopic lipid deposition contribute to obesity-related insulin resistance (IR). ... more Inflammation and ectopic lipid deposition contribute to obesity-related insulin resistance (IR). Studies have shown that deficiency of the proinflammatory cytokine tumor necrosis factor-α (TNFα) protects against the IR induced by a high-fat diet (HFD). We aimed to evaluate the relationship between HFD-related inflammation and lipid deposition in skeletal muscle and liver. Wild-type (WT) and TNFα-deficient (TNFα-KO) mice were subjected to an HFD for 12 weeks. A glucose tolerance test was performed to evaluate IR. Inflammatory status was assessed by measuring plasma and tissue transcript levels of cytokines. Lipid intermediate concentrations were measured in plasma, muscle and liver. The expression of genes involved in fatty acid transport, synthesis and oxidation was analyzed in adipose tissue, muscle and liver. HFD induced a higher body weight gain in TNFα-KO mice than in WT mice. The weight of epididymal and abdominal adipose tissues was twofold lower in WT mice than in TNFα-KO mice, whereas liver weight was significantly heavier in WT mice. IR, systemic and adipose tissue inflammation, and plasma nonesterified fatty acid levels were reduced in TNFα-KO mice fed an HFD. TNFα deficiency improved fatty acid metabolism and had a protective effect against lipid deposition, inflammation and fibrosis associated with HFD in liver but had no impact on these markers in muscle. Our data suggest that in an HFD context, TNFα deficiency reduced hepatic lipid accumulation through two mechanisms: an increase in adipose tissue storage capacity and a decrease in fatty acid uptake and synthesis in the liver.
Post-translational oxidative protein modifications which are more marked during aging and/or high... more Post-translational oxidative protein modifications which are more marked during aging and/or high-calorie (HC) diets affect protein function and metabolism. Protein function and metabolism are different according to the type of muscle proteins. Oxidative muscle protein modifications may thus be associated with agerelated sarcopenia, and HC may be implicated in the development of sarcopenia by emphasizing protein modifications. Understanding the role of protein modifications in the process of sarcopenia and metabolism associated with a high fat diet may be elucidated by investigations with skeletal muscle protein subfractionations. To study this hypothesis, carbonylated protein (CP) and 3-nitrotyrosine (3-NT) levels were measured in mixed, sarcoplasmic, myofibrillar and mitochondrial protein fractions of quadriceps in rats aged 6 months (A) and 25 months (O) fed a normal calorie (NC) or HC diet for 3 months (AN, AH, ON, OH n = 7-8). Muscle weight was lower in the older rats (AN: 0.79 ± 0.03 g, ON: 0.43 ± 0.12 g, P b 0.05), but no HC effect was observed. CP did not differ between groups while 3-NT accumulated significantly in ON compared with AN, especially in mitochondria (2.4 ± 0.5, 1.3 ± 0.1, 1.9 ± 0.4, 2.9 ± 1.2 -fold in mixed, sarcoplasmic, myofibrillar and mitochondrial fractions respectively, P b 0.05). 3-NT in mixed protein was negatively correlated with muscle mass (r 2 = − 0.812). 3-NT accumulation during HC was observed only in specific proteins of mitochondria (100 kDa) (1.0 ± 0.6, 1.7 ± 0.9, 3.3 ± 1.4 and 7.0 ± 2.5 -fold in AN, AH, ON and OH, respectively, P b 0.05). Hence cumulative 3-NT in skeletal muscle protein appears associated with the development of age-related muscle loss. Mitochondrial proteins are more prone to nitration during aging and nutritional stress.
ABSTRACT Le vieillissement se caractérise par une perte de masse musculaire et un gain de masse g... more ABSTRACT Le vieillissement se caractérise par une perte de masse musculaire et un gain de masse grasse notamment viscérale. L’augmentation de la résistance à l’insuline due à l’obésité viscérale peut s’expliquer par deux phénomènes, la lipotoxicité et l’inflammation. L’objectif était de mesurer l’effet de l’obésité au cours du vieillissement sur la sensibilité à l’insuline, l’inflammation et la lipotoxicité et les conséquences sur la synthèse protéique musculaire.Matériels et méthodesDurant 10 semaines, 34 rats WISTAR âgés de 6 ou 25 mois ont reçu un régime normo- (JNL, VNL) ou hyper-lipidique/hyper-calorique (JHL, VHL). Un test de tolérance au glucose a été réalisé afin d’évaluer la sensibilité à l’insuline. Le profil inflammatoire a été évalué en mesurant la concentration plasmatique du récepteur soluble du TNF-α (sTNF-R2). Les taux de céramides, de diacylglycerols et de triglycérides ont été dosés au sein des muscles. La synthèse protéique musculaire (FSR) a été calculée à partir de l’enrichissement en [13C] valine des protéines.RésultatsLe groupe VHL était le plus insulino-résistant (p < 0,05 vs. JNL, JHL et VNL). La concentration plasmatique en sTNF-R2 pour le groupe VHL était supérieure à celle des JNL, JHL, et VNL (p < 0,05). La concentration des dérivés lipidiques musculaires était augmentée dans le groupe VHL comparativement aux trois autres groupes (p < 0,05). Le FSR des protéines musculaires était diminué de 18,6% dans le groupe VHL (p < 0,05) comparativement au groupe VNL.Conclusion Nous observons une accumulation liée à l’âge des dérivés lipidiques au sein des muscles des rats; ce phénomène étant aggravé par le régime HL. L’augmentation de l’inflammation chez les VHL pourrait être responsable de la dérégulation de la fonction tampon du tissu adipeux entraînant un stockage des lipides au sein du muscle. Les conséquences seraient une augmentation de l’insulinorésistance et une diminution de la synthèse protéique musculaire.
In cancer cachexia, muscle depletion is related to morbidity and mortality. Muscle-wasting mechan... more In cancer cachexia, muscle depletion is related to morbidity and mortality. Muscle-wasting mechanisms in cancer patients are not fully understood. We investigated the involvement of the proteolytic systems (proteasome, autophagic-lysosomal, calpain, and caspase) in muscle wasting during cancer cachexia. Esophageal cancer patients [n = 14; mean ± SD age: 64.1 ± 6.6 y] and weight-stable control patients undergoing reflux surgery (n = 8; age: 57.5 ± 5.8 y) were included. Enzymatic activities were measured in the vastus lateralis and diaphragm. Protein expressions were also measured in the vastus lateralis of control (n = 7) and cancer (n = 8) patients. Proteasome, calpain, and caspase 3 activities in the vastus lateralis and diaphragm muscles did not differ between the 2 groups. Cathepsin B and L activities were 90% (± SD) [2.4 ± 0.2 compared with 1.3 ± 0.2 pmol 7-amido-4-methylcoumarin (AMC) · μg protein⁻¹ · min⁻¹; P < 0.001] and 115% (5.3 ± 0.4 compared with 2.5 ± 0.3 pmol AMC · μg protein⁻¹ · min⁻¹; P < 0.001) greater, respectively, in the vastus lateralis of cancer patients than in that of control subjects. We observed (in conjunction with increased lysosomal protease activities) higher microtubule-associated protein 1 light chain 3B-II/I ratios (0.14 ± 0.08 compared with 0.04 ± 0.04) and cathepsin B and L expressions in the vastus lateralis of cancer patients than in that of control subjects (P < 0.05). Protein expression of p62 in the vastus lateralis did not differ between the 2 groups. The autophagic-lysosomal pathway in the skeletal muscle of cancer patients was modified, whereas other proteolytic systems were unchanged. These findings suggest involvement of the autophagic-lysosomal proteolytic system during cancer cachexia development in humans.
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.
ABSTRACT Introduction et but de l’étude Le vieillissement est caractérisé par une accumulation et... more ABSTRACT Introduction et but de l’étude Le vieillissement est caractérisé par une accumulation et une redistribution de la masse grasse corporelle avec une augmentation importante des dépôts adipeux intra-abdominaux. Ce phénomène pourrait contribuer aux perturbations de l’accrétion protéique musculaire liées à l’âge, en particulier chez le sujet âgé obèse, débouchant sur le syndrome d’obésité sarcopénique. L’objectif de cette étude était d’évaluer, chez le rat jeune ou âgé, l’effet de l’accroissement de l’adiposité par un régime hyper-lipidique et hyper-calorique (HL), sur la production de cytokines pro- et anti-inflammatoires, l’insulino-sensibilité (IoS) et la vitesse de synthèse des protéines musculaires et adipeuses (FSR). Matériel et méthodes 34 rats Wistar mâles âgés de 6 (J) ou 25 (V) mois ont été repartis en 4 groupes et ont reçu un régime normo-(JNL, VNL) ou hyper-lipidique/hyper-calorique (JHL, VHL) durant 10 semaines. Un test de tolérance au glucose (IPGTT) a été réalisé afin d’évaluer l’IoS. Le profil inflammatoire a été évalué en mesurant la concentration plasmatique (ELISA) du récepteur soluble du TNFa (sTNF-R2) et la quantité d’ARNm (qRT-PCR) de l’adiponectine dans le tissu adipeux. Le FSR a été calculé à partir de l’enrichissement en [13C] valine des protéines musculaires (tibialis anterior) et adipeuses (tissu adipeux abdominal) par spectrométrie de masse. Résultats L’IoS était diminuée chez les vieux rats soumis à un régime HL (VHF vs VNL, JNL, JHF ; p<0,05). L’expression des ARNm de l’adiponectine dans le tissu adipeux était diminuée de moitié chez les rats VHL par rapport au groupe contrôle (p<0,05) mais n’était pas modifiée chez les animaux plus jeunes. Une élévation de 37 % des taux plasmatiques en sTNF-R2, marqueur de la secretion et de l’activité du TNFa, était observée chez les rats âgés soumis au régime HL (VHF vs VNL ; p<0,05) mais n’étaient pas modifiés chez les jeunes rats. Le FSR du tissu adipeux était diminué uniquement par l’âge (JNL vs VNL, p<0,05). Une réduction de 23 % des FSR des protéines musculaires totales était observée seulement dans le groupe VHL par rapport aux rats témoins (p<0,05), sans aucun changement chez le animaux plus jeunes. Conclusions L’augmentation de l’adiposité chez les rats âgés induite par le régime HL s’accompagne d’une augmentation de l’inflammation, d’une insulinorésistance, et d’une réduction de la synthèse protéique musculaire. Ce défaut d’adaptation du métabolisme protéique préférentiellement musculaire en réponse au régime HL pourrait participer à l’accélération de la perte protéique musculaire et favoriser l’apparition d’une obésité sarcopénique.
Background & aims: Age-related inflammation and insulin resistance (IR) have been implicated in t... more Background & aims: Age-related inflammation and insulin resistance (IR) have been implicated in the inability of old muscles to properly respond to anabolic stimuli such as amino acids (AA) or insulin. Since fatty acids can modulate inflammation and IR in muscle cells, we investigated the effect of palmitateenriched diet and oleate-enriched diet on inflammation, IR and muscle protein synthesis (MPS) rate in old rats. Methods: Twenty-four 25-month-old rats were fed either a control diet (OC), an oleate-enriched diet (HFO) or a palmitate-enriched diet (HFP) for 16 weeks. MPS using labeled amino acids and mTOR activation were assessed after AA and insulin anabolic stimulation to mimic postprandial state. Results: IR and systemic and adipose tissue inflammation (TNFa and IL1b) were improved in the HFO group. Muscle genes controlling mitochondrial b-oxidation (PPARs, MCAD and CPT-1b) were upregulated in the HFO group. AA and insulin-stimulated MPS in the HFO group only, and this stimulation was related to activation of the Akt/mTOR pathway. Conclusions: The age-related MPS response to anabolic signals was improved in rats fed an oleateenriched diet. This effect was related to activation of muscle oxidative pathways, lower IR, and a decrease in inflammation.
Cancer cachexia is a complex syndrome generated by interaction between the host and tumour cells ... more Cancer cachexia is a complex syndrome generated by interaction between the host and tumour cells with a background of treatment effects and toxicity. The complexity of the physiological pathways likely involved in cancer cachexia necessitates a holistic view of the relevant biology. Emergent properties are characteristic of complex systems with the result that the end result is more than the sum of its parts. Recognition of the importance of emergent properties in biology led to the concept of systems biology wherein a holistic approach is taken to the biology at hand. Systems biology approaches will therefore play an important role in work to uncover key mechanisms with therapeutic potential in cancer cachexia. The 'omics' technologies provide a global view of biological systems. Genomics, transcriptomics, proteomics, lipidomics and metabolomics approaches all have application in the study of cancer cachexia to generate systems level models of the behaviour of this syndrome. The current work reviews recent applications of these technologies to muscle atrophy in general and cancer cachexia in particular with a view to progress towards integration of these approaches to better understand the pathology and potential treatment pathways in cancer cachexia.
Applied Physiology, Nutrition, and Metabolism, 2015
The measurement of mitochondrial protein synthesis after food ingestion, contractile activity, an... more The measurement of mitochondrial protein synthesis after food ingestion, contractile activity, and/or disease is often used to provide insight into skeletal muscle adaptations that occur in the longer term. Studies have shown that protein ingestion stimulates mitochondrial protein synthesis in human skeletal muscle. Minor differences in the stimulation of mitochondrial protein synthesis occur after a single bout of resistance or endurance exercise. There appear to be no measurable differences in mitochondrial protein synthesis between critically ill patients and aged-matched controls. However, the mitochondrial protein synthetic response is reduced at a more advanced age. In this paper, we discuss the challenges involved in the measurement of human skeletal muscle mitochondrial protein synthesis rates based on stable isotope amino acid tracer methods. Practical guidelines are discussed to improve the reliability of the measurement of mitochondrial protein synthesis rates. The value of the measurement of mitochondrial protein synthesis after a single meal or exercise bout on the prediction of the longer term skeletal muscle mass and performance outcomes in both the healthy and disease populations requires more work, but we emphasize that the measurements need to be reliable to be of any value to the field.
Obesity and aging are characterized by decreased insulin sensitivity (IS) and muscle protein synt... more Obesity and aging are characterized by decreased insulin sensitivity (IS) and muscle protein synthesis. Intramuscular ceramide accumulation has been implicated in insulin resistance during obesity. We aimed to measure IS, muscle ceramide level, protein synthesis, and activation of intracellular signaling pathways involved in translation initiation in male Wistar young (YR, 6-month) and old (OR, 25-month) rats receiving a low-(LFD) or a high-fat diet (HFD) for 10 weeks. A corresponding cellular approach using C2C12 myotubes treated with palmitate to induce intracellular ceramide deposition was taken. A decreased ability of adipose tissue to store lipids together with a reduced adipocyte diameter and a development of fibrosis were observed in OR after the HFD. Consequently, OR fed the HFD were insulin resistant, showed a strong increase in intramuscular ceramide level and a decrease in muscle protein synthesis associated with increased eIF2a phosphorylation. The accumulation of intramuscular lipids placed a lipid burden on mitochondria and created a disconnect between metabolic and regulating pathways in skeletal muscles of OR. In C2C12 cells, palmitate-induced ceramide accumulation was associated with a decreased protein synthesis together with upregulated eIF2a phosphorylation. In conclusion, a reduced ability to expand adipose tissues was found in OR, reflecting a lower lipid buffering capacity. Muscle mitochondrial activity was affected in OR conferring a reduced ability to oxidize fatty acids entering the muscle cell. Hence, OR were more prone to ectopic muscle lipid accumulation than YR, leading to decreased muscle protein anabolism. This metabolic change is a potential therapeutic target to counter sarcopenic obesity.
The increasing prevalence of obesity among elderly people has led to the definition of the concep... more The increasing prevalence of obesity among elderly people has led to the definition of the concept of sarcopenic obesity. This concept is defined as the potential to combine muscle metabolic changes associated with both aging and obesity. Several definitions have been proposed, but the absence of a consensus led to great variability in the prevalence of this phenomenon in literature.
Inflammation and ectopic lipid deposition contribute to obesity-related insulin resistance (IR). ... more Inflammation and ectopic lipid deposition contribute to obesity-related insulin resistance (IR). Studies have shown that deficiency of the proinflammatory cytokine tumor necrosis factor-α (TNFα) protects against the IR induced by a high-fat diet (HFD). We aimed to evaluate the relationship between HFD-related inflammation and lipid deposition in skeletal muscle and liver. Wild-type (WT) and TNFα-deficient (TNFα-KO) mice were subjected to an HFD for 12 weeks. A glucose tolerance test was performed to evaluate IR. Inflammatory status was assessed by measuring plasma and tissue transcript levels of cytokines. Lipid intermediate concentrations were measured in plasma, muscle and liver. The expression of genes involved in fatty acid transport, synthesis and oxidation was analyzed in adipose tissue, muscle and liver. HFD induced a higher body weight gain in TNFα-KO mice than in WT mice. The weight of epididymal and abdominal adipose tissues was twofold lower in WT mice than in TNFα-KO mice, whereas liver weight was significantly heavier in WT mice. IR, systemic and adipose tissue inflammation, and plasma nonesterified fatty acid levels were reduced in TNFα-KO mice fed an HFD. TNFα deficiency improved fatty acid metabolism and had a protective effect against lipid deposition, inflammation and fibrosis associated with HFD in liver but had no impact on these markers in muscle. Our data suggest that in an HFD context, TNFα deficiency reduced hepatic lipid accumulation through two mechanisms: an increase in adipose tissue storage capacity and a decrease in fatty acid uptake and synthesis in the liver.
Post-translational oxidative protein modifications which are more marked during aging and/or high... more Post-translational oxidative protein modifications which are more marked during aging and/or high-calorie (HC) diets affect protein function and metabolism. Protein function and metabolism are different according to the type of muscle proteins. Oxidative muscle protein modifications may thus be associated with agerelated sarcopenia, and HC may be implicated in the development of sarcopenia by emphasizing protein modifications. Understanding the role of protein modifications in the process of sarcopenia and metabolism associated with a high fat diet may be elucidated by investigations with skeletal muscle protein subfractionations. To study this hypothesis, carbonylated protein (CP) and 3-nitrotyrosine (3-NT) levels were measured in mixed, sarcoplasmic, myofibrillar and mitochondrial protein fractions of quadriceps in rats aged 6 months (A) and 25 months (O) fed a normal calorie (NC) or HC diet for 3 months (AN, AH, ON, OH n = 7-8). Muscle weight was lower in the older rats (AN: 0.79 ± 0.03 g, ON: 0.43 ± 0.12 g, P b 0.05), but no HC effect was observed. CP did not differ between groups while 3-NT accumulated significantly in ON compared with AN, especially in mitochondria (2.4 ± 0.5, 1.3 ± 0.1, 1.9 ± 0.4, 2.9 ± 1.2 -fold in mixed, sarcoplasmic, myofibrillar and mitochondrial fractions respectively, P b 0.05). 3-NT in mixed protein was negatively correlated with muscle mass (r 2 = − 0.812). 3-NT accumulation during HC was observed only in specific proteins of mitochondria (100 kDa) (1.0 ± 0.6, 1.7 ± 0.9, 3.3 ± 1.4 and 7.0 ± 2.5 -fold in AN, AH, ON and OH, respectively, P b 0.05). Hence cumulative 3-NT in skeletal muscle protein appears associated with the development of age-related muscle loss. Mitochondrial proteins are more prone to nitration during aging and nutritional stress.
ABSTRACT Le vieillissement se caractérise par une perte de masse musculaire et un gain de masse g... more ABSTRACT Le vieillissement se caractérise par une perte de masse musculaire et un gain de masse grasse notamment viscérale. L’augmentation de la résistance à l’insuline due à l’obésité viscérale peut s’expliquer par deux phénomènes, la lipotoxicité et l’inflammation. L’objectif était de mesurer l’effet de l’obésité au cours du vieillissement sur la sensibilité à l’insuline, l’inflammation et la lipotoxicité et les conséquences sur la synthèse protéique musculaire.Matériels et méthodesDurant 10 semaines, 34 rats WISTAR âgés de 6 ou 25 mois ont reçu un régime normo- (JNL, VNL) ou hyper-lipidique/hyper-calorique (JHL, VHL). Un test de tolérance au glucose a été réalisé afin d’évaluer la sensibilité à l’insuline. Le profil inflammatoire a été évalué en mesurant la concentration plasmatique du récepteur soluble du TNF-α (sTNF-R2). Les taux de céramides, de diacylglycerols et de triglycérides ont été dosés au sein des muscles. La synthèse protéique musculaire (FSR) a été calculée à partir de l’enrichissement en [13C] valine des protéines.RésultatsLe groupe VHL était le plus insulino-résistant (p < 0,05 vs. JNL, JHL et VNL). La concentration plasmatique en sTNF-R2 pour le groupe VHL était supérieure à celle des JNL, JHL, et VNL (p < 0,05). La concentration des dérivés lipidiques musculaires était augmentée dans le groupe VHL comparativement aux trois autres groupes (p < 0,05). Le FSR des protéines musculaires était diminué de 18,6% dans le groupe VHL (p < 0,05) comparativement au groupe VNL.Conclusion Nous observons une accumulation liée à l’âge des dérivés lipidiques au sein des muscles des rats; ce phénomène étant aggravé par le régime HL. L’augmentation de l’inflammation chez les VHL pourrait être responsable de la dérégulation de la fonction tampon du tissu adipeux entraînant un stockage des lipides au sein du muscle. Les conséquences seraient une augmentation de l’insulinorésistance et une diminution de la synthèse protéique musculaire.
In cancer cachexia, muscle depletion is related to morbidity and mortality. Muscle-wasting mechan... more In cancer cachexia, muscle depletion is related to morbidity and mortality. Muscle-wasting mechanisms in cancer patients are not fully understood. We investigated the involvement of the proteolytic systems (proteasome, autophagic-lysosomal, calpain, and caspase) in muscle wasting during cancer cachexia. Esophageal cancer patients [n = 14; mean ± SD age: 64.1 ± 6.6 y] and weight-stable control patients undergoing reflux surgery (n = 8; age: 57.5 ± 5.8 y) were included. Enzymatic activities were measured in the vastus lateralis and diaphragm. Protein expressions were also measured in the vastus lateralis of control (n = 7) and cancer (n = 8) patients. Proteasome, calpain, and caspase 3 activities in the vastus lateralis and diaphragm muscles did not differ between the 2 groups. Cathepsin B and L activities were 90% (± SD) [2.4 ± 0.2 compared with 1.3 ± 0.2 pmol 7-amido-4-methylcoumarin (AMC) · μg protein⁻¹ · min⁻¹; P < 0.001] and 115% (5.3 ± 0.4 compared with 2.5 ± 0.3 pmol AMC · μg protein⁻¹ · min⁻¹; P < 0.001) greater, respectively, in the vastus lateralis of cancer patients than in that of control subjects. We observed (in conjunction with increased lysosomal protease activities) higher microtubule-associated protein 1 light chain 3B-II/I ratios (0.14 ± 0.08 compared with 0.04 ± 0.04) and cathepsin B and L expressions in the vastus lateralis of cancer patients than in that of control subjects (P < 0.05). Protein expression of p62 in the vastus lateralis did not differ between the 2 groups. The autophagic-lysosomal pathway in the skeletal muscle of cancer patients was modified, whereas other proteolytic systems were unchanged. These findings suggest involvement of the autophagic-lysosomal proteolytic system during cancer cachexia development in humans.
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.
ABSTRACT Introduction et but de l’étude Le vieillissement est caractérisé par une accumulation et... more ABSTRACT Introduction et but de l’étude Le vieillissement est caractérisé par une accumulation et une redistribution de la masse grasse corporelle avec une augmentation importante des dépôts adipeux intra-abdominaux. Ce phénomène pourrait contribuer aux perturbations de l’accrétion protéique musculaire liées à l’âge, en particulier chez le sujet âgé obèse, débouchant sur le syndrome d’obésité sarcopénique. L’objectif de cette étude était d’évaluer, chez le rat jeune ou âgé, l’effet de l’accroissement de l’adiposité par un régime hyper-lipidique et hyper-calorique (HL), sur la production de cytokines pro- et anti-inflammatoires, l’insulino-sensibilité (IoS) et la vitesse de synthèse des protéines musculaires et adipeuses (FSR). Matériel et méthodes 34 rats Wistar mâles âgés de 6 (J) ou 25 (V) mois ont été repartis en 4 groupes et ont reçu un régime normo-(JNL, VNL) ou hyper-lipidique/hyper-calorique (JHL, VHL) durant 10 semaines. Un test de tolérance au glucose (IPGTT) a été réalisé afin d’évaluer l’IoS. Le profil inflammatoire a été évalué en mesurant la concentration plasmatique (ELISA) du récepteur soluble du TNFa (sTNF-R2) et la quantité d’ARNm (qRT-PCR) de l’adiponectine dans le tissu adipeux. Le FSR a été calculé à partir de l’enrichissement en [13C] valine des protéines musculaires (tibialis anterior) et adipeuses (tissu adipeux abdominal) par spectrométrie de masse. Résultats L’IoS était diminuée chez les vieux rats soumis à un régime HL (VHF vs VNL, JNL, JHF ; p<0,05). L’expression des ARNm de l’adiponectine dans le tissu adipeux était diminuée de moitié chez les rats VHL par rapport au groupe contrôle (p<0,05) mais n’était pas modifiée chez les animaux plus jeunes. Une élévation de 37 % des taux plasmatiques en sTNF-R2, marqueur de la secretion et de l’activité du TNFa, était observée chez les rats âgés soumis au régime HL (VHF vs VNL ; p<0,05) mais n’étaient pas modifiés chez les jeunes rats. Le FSR du tissu adipeux était diminué uniquement par l’âge (JNL vs VNL, p<0,05). Une réduction de 23 % des FSR des protéines musculaires totales était observée seulement dans le groupe VHL par rapport aux rats témoins (p<0,05), sans aucun changement chez le animaux plus jeunes. Conclusions L’augmentation de l’adiposité chez les rats âgés induite par le régime HL s’accompagne d’une augmentation de l’inflammation, d’une insulinorésistance, et d’une réduction de la synthèse protéique musculaire. Ce défaut d’adaptation du métabolisme protéique préférentiellement musculaire en réponse au régime HL pourrait participer à l’accélération de la perte protéique musculaire et favoriser l’apparition d’une obésité sarcopénique.
Background & aims: Age-related inflammation and insulin resistance (IR) have been implicated in t... more Background & aims: Age-related inflammation and insulin resistance (IR) have been implicated in the inability of old muscles to properly respond to anabolic stimuli such as amino acids (AA) or insulin. Since fatty acids can modulate inflammation and IR in muscle cells, we investigated the effect of palmitateenriched diet and oleate-enriched diet on inflammation, IR and muscle protein synthesis (MPS) rate in old rats. Methods: Twenty-four 25-month-old rats were fed either a control diet (OC), an oleate-enriched diet (HFO) or a palmitate-enriched diet (HFP) for 16 weeks. MPS using labeled amino acids and mTOR activation were assessed after AA and insulin anabolic stimulation to mimic postprandial state. Results: IR and systemic and adipose tissue inflammation (TNFa and IL1b) were improved in the HFO group. Muscle genes controlling mitochondrial b-oxidation (PPARs, MCAD and CPT-1b) were upregulated in the HFO group. AA and insulin-stimulated MPS in the HFO group only, and this stimulation was related to activation of the Akt/mTOR pathway. Conclusions: The age-related MPS response to anabolic signals was improved in rats fed an oleateenriched diet. This effect was related to activation of muscle oxidative pathways, lower IR, and a decrease in inflammation.
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