Russell Hepple | McGill University (original) (raw)
Papers by Russell Hepple
Applied Physiology Nutrition and Metabolism-physiologie Appliquee Nutrition Et Metabolisme, 2008
Aging is associated with a progressive decline in the capacity for physical activity. Central to ... more Aging is associated with a progressive decline in the capacity for physical activity. Central to this decline is a reduction in the maximal rate of oxygen utilization, or VO2 max. This critical perspective examines the roles played by the factors that determine the rate of muscle oxygen delivery versus those that determine the utilization of oxygen by muscle as a means of probing the reasons for VO2 max decline with aging. Reductions in muscle oxygen delivery, principally due to reduced cardiac output and perhaps also a maldistribution of cardiac output, appear to play the dominant role up until late middle age. On the other hand, there is a decline in skeletal muscle oxidative capacity with aging, due in part to mitochondrial dysfunction, which appears to play a particularly important role in extreme old age (senescence) where skeletal muscle VO2 max is observed to decline by approximately 50% even under conditions of similar oxygen delivery as young adult muscle. It is noteworthy that at least the structural aspects of the capillary bed do not appear to be reduced in a manner that would compromise the capacity for muscle oxygen diffusion even in senescence.
We investigated if calorie restriction (CR) preserved skeletal muscle oxidative capacity with agi... more We investigated if calorie restriction (CR) preserved skeletal muscle oxidative capacity with aging after accounting for life span extension by CR, and determined if mitochondrial content, mitochondrial DNA integrity, and peroxisome proliferator-activated receptor gamma coactivator- 1a (PGC-1a) were involved. Ad libitum-fed (AL) and CR animals representing young adult, late middle age, and senescence were studied. Whereas citrate synthase and complex
Cell Metabolism, 2015
The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which... more The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which PA prevents disease and improves health outcomes are poorly understood. To identify major gaps in knowledge and potential strategies for catalyzing progress in the field, the NIH convened a workshop in late October 2014 entitled "Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits." Presentations and discussions emphasized the challenges imposed by the integrative and intermittent nature of PA, the tremendous discovery potential of applying…
PLoS ONE, 2014
PGC-1a regulates critical processes in muscle physiology, including mitochondrial biogenesis, lip... more PGC-1a regulates critical processes in muscle physiology, including mitochondrial biogenesis, lipid metabolism and angiogenesis. Furthermore, PGC-1a was suggested as an important regulator of fiber type determination. However, whether a muscle fiber type-specific PGC-1a content exists, whether PGC-1a content relates to basal levels of mitochondrial content, and whether such relationships are preserved between humans and classically used rodent models are all questions that have been either poorly addressed or never investigated. To address these issues, we investigated the fiber type-specific content of PGC-1a and its relationship to basal mitochondrial content in mouse, rat and human muscles using in situ immunolabeling and histochemical methods on muscle serial cross-sections. Whereas type IIa fibers exhibited the highest PGC-1a in all three species, other fiber types displayed a hierarchy of type IIx.I.IIb in mouse, type I = IIx. IIb in rat, and type IIx.I in human. In terms of mitochondrial content, we observed a hierarchy of IIa.IIx.I.IIb in mouse, IIa .I.IIx. IIb in rat, and I.IIa. IIx in human skeletal muscle. We also found in rat skeletal muscle that type I fibers displayed the highest capillarization followed by type IIa .IIx.IIb. Finally, we found in human skeletal muscle that type I fibers display the highest lipid content, followed by type IIa.IIx. Altogether, our results reveal that (i) the fiber type-specific PGC-1a and mitochondrial contents were only matched in mouse, (ii) the patterns of PGC-1a and mitochondrial contents observed in mice and rats do not correspond to that seen in humans in several respects, and (iii) the classical phenotypes thought to be regulated by PGC-1a do not vary exclusively as a function of PGC-1a content in rat and human muscles.
PLoS ONE, 2012
The aging heart is characterized by a progressive decline in contractile function and diastolic r... more The aging heart is characterized by a progressive decline in contractile function and diastolic relaxation. Amongst the factors implicated in these changes is a progressive replacement fibrosis secondary to cardiomyocyte death, oxidative damage, and energetic deficit, each of which may be secondary to impaired mitochondrial function. Here, we performed an in-depth examination of mitochondrial function in saponin-permeabilized cardiomyocyte bundles, a preparation where all mitochondria are represented and their structure intact, from young adult (YA) and senescent (SEN) rats (n = 8 per group). When accounting for increased fibrosis (+19%, P<0.01) and proportional decrease in citrate synthase activity in the SEN myocardium (-23%, P<0.05), mitochondrial respiration and reactive oxygen species (H(2)O(2)) emission across a range of energized states was similar between age groups. Accordingly, the abundance of electron transport chain proteins was also unchanged. Likewise, except for CuZnSOD (-37%, P<0.05), the activity of antioxidant enzymes was unaltered with aging. Although time to mitochondrial permeability transition pore (mPTP) opening was decreased (-25%, P<0.05) in the SEN heart, suggesting sensitization to apoptotic stimuli, this was not associated with a difference in apoptotic index measured by ELISA. Collectively, our results suggest that the function of existing cardiac ventricular mitochondria is relatively preserved in SEN rat heart when measured in permeabilized cells.
Engineering Structures, 2011
The senescent heart has decreased systolic and diastolic functions, both of which could be relate... more The senescent heart has decreased systolic and diastolic functions, both of which could be related to alterations in cardiac sarcoplasmic reticulum (SR) calcium (Ca2+) handling. The purpose of this study was to determine if SR protein content and rates of Ca2+ release and uptake and ATPase activity are lower in the senescent (34–36mo) Fisher 344×Brown-Norway F1 hybrid rat heart and
Medicine & Science in Sports & Exercise, 2010
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2004
Although mitochondrial DNA damage accumulates in aging skeletal muscles, how this relates to the ... more Although mitochondrial DNA damage accumulates in aging skeletal muscles, how this relates to the decline in muscle mass-specific skeletal muscle aerobic function is unknown. We used a pump-perfused rat hind-limb model to examine maximal aerobic performance ( _ VO 2max ) in young adult (YA; 8-9-month-old), late middle aged (LMA; 28-30-month-old) and senescent (SEN; 36month-old) Fischer 344 3 Brown Norway F1-hybrid rats at matched rates of convective O 2 delivery (QO 2 ). Despite similar muscle QO 2 during a 4-minute contraction bout, muscle massspecific _ VO 2max was reduced in LMA (15%) and SEN (52%) versus YA. In plantaris muscle homogenates, nested polymerase chain reaction revealed an increased frequency of mitochondrial DNA deletions in the older animals. A greater reduction in the flux through electron transport chain complexes I-III than citrate synthase activity in the older animals suggests mitochondrial dysfunction consequent to mitochondrial DNA damage with aging. These results support the hypothesis that a reduced oxidative capacity, due in part to age-related mitochondrial dysfunction, contributes to the decline in aerobic performance in aging skeletal muscles.
Experimental Gerontology, 2010
Age-related loss of muscle mass and function exhibits a marked acceleration from late middle age ... more Age-related loss of muscle mass and function exhibits a marked acceleration from late middle age to senescence and exercise training is one method that has been proposed to slow this process. The purpose of this study was to determine if long-term treadmill exercise training initiated at late middle age could increase endogenous antioxidant enzyme activity and attenuate the loss of skeletal muscle contractile properties in the gastrocnemius/plantaris (GAS/Plan) and soleus (SOL) muscles of senescent rats (34-36 mo) through a decrease in oxidative damage. Male Fisher 344 × Brown Norway F1-hybrid rats underwent 5-7 mo of treadmill training beginning at late middle age (29 mo). A 7 mo sedentary adult group was used to investigate age-related changes. Aging caused an increase in antioxidant enzyme activities; however, only SOD activity was further increased with exercise training. Exercise training did not attenuate the decrease in twitch or tetanic tension of the GAS/Plan or SOL. It did, however, prevent the increase in twitch half relaxation time of the SOL muscle only. Oxidative damage, as reflected in carbonyl content, was increased with age and even further with exercise training in the GAS muscle. Muscle fibre cross sectional area was decreased with age and even further with exercise training. Interestingly, small muscle fibres showed the highest accumulation of carbonyls. Overall, despite an augmentation of select antioxidant enzyme activities, exercise training from late middle age through to senescence had minimal benefits for muscle contractile properties, perhaps in part due to exacerbated oxidation.
Autophagy, 2013
autophagy is an important proteolytic pathway in skeletal muscles. The roles of muscle fiber type... more autophagy is an important proteolytic pathway in skeletal muscles. The roles of muscle fiber type composition and oxidative capacity remain unknown in relation to autophagy. The diaphragm (Dia) is a fast-twitch muscle fiber with high oxidative capacity, the tibialis anterior (Ta) muscle is a fast-twitch muscle fiber with low oxidative capacity, and the soleus muscle (sol) is a slow-twitch muscle with high oxidative capacity. We hypothesized that oxidative capacity is a major determinant of autophagy in skeletal muscles. Following acute (24 h) starvation of adult c57/Bl6 mice, each muscle was assessed for autophagy and compared with controls. autophagy was measured by monitoring autophagic flux following leupeptin (20 mg/kg) or colchicine (0.4 mg/kg/day) injection. oxidative capacity was measured by monitoring citrate synthase activity. in control mice, autophagic flux values were significantly greater in the Ta than in the Dia and sol. in acutely starved mice, autophagic flux increased, most markedly in the Ta, and several key autophagy-related genes were significantly induced. in both control and starved mice, there was a negative linear correlation of autophagic flux with citrate synthase activity. starvation significantly induced aMPK phosphorylation and inhibited aKT and rPs6KB1 phosphorylation, again most markedly in the Ta. starvation induced Foxo1, Foxo3 and Foxo4 expression and attenuated the phosphorylation of their gene products. We conclude that both basal and starvationinduced autophagic flux are greater in skeletal muscles with low oxidative capacity as compared with those with high oxidative capacity and that this difference is mediated through selective activation of the aMPK pathway and inhibition of the aKT-MTor pathways.
Aging Cell, 2010
Mitochondria regulate cellular bioenergetics and apoptosis and have been implicated in aging. How... more Mitochondria regulate cellular bioenergetics and apoptosis and have been implicated in aging. However, it remains unclear whether age-related loss of muscle mass, known as sarcopenia, is associated with abnormal mitochondrial function. Two technically different approaches have mainly been used to measure mitochondrial function: isolated mitochondria and permeabilized myofiber bundles, but the reliability of these measures in the context of sarcopenia has not been systematically assessed before. A key difference between these approaches is that contrary to isolated mitochondria, permeabilized bundles contain the totality of fiber mitochondria where normal mitochondrial morphology and intracellular interactions are preserved. Using the gastrocnemius muscle from young adult and senescent rats, we show marked effects of aging on three primary indices of mitochondrial function (respiration, H 2 O 2 emission, sensitivity of permeability transition pore to Ca 2+ ) when measured in isolated mitochondria, but to a much lesser degree when measured in permeabilized bundles. Our results clearly demonstrate that mitochondrial isolation procedures typically employed to study aged muscles expose functional impairments not seen in situ. We conclude that aging is associated with more modest changes in mitochondrial function in sarcopenic muscle than suggested previously from isolated organelle studies.
Applied Physiology Nutrition and Metabolism-physiologie Appliquee Nutrition Et Metabolisme, 2008
Aging is associated with a progressive decline in the capacity for physical activity. Central to ... more Aging is associated with a progressive decline in the capacity for physical activity. Central to this decline is a reduction in the maximal rate of oxygen utilization, or VO2 max. This critical perspective examines the roles played by the factors that determine the rate of muscle oxygen delivery versus those that determine the utilization of oxygen by muscle as a means of probing the reasons for VO2 max decline with aging. Reductions in muscle oxygen delivery, principally due to reduced cardiac output and perhaps also a maldistribution of cardiac output, appear to play the dominant role up until late middle age. On the other hand, there is a decline in skeletal muscle oxidative capacity with aging, due in part to mitochondrial dysfunction, which appears to play a particularly important role in extreme old age (senescence) where skeletal muscle VO2 max is observed to decline by approximately 50% even under conditions of similar oxygen delivery as young adult muscle. It is noteworthy that at least the structural aspects of the capillary bed do not appear to be reduced in a manner that would compromise the capacity for muscle oxygen diffusion even in senescence.
We investigated if calorie restriction (CR) preserved skeletal muscle oxidative capacity with agi... more We investigated if calorie restriction (CR) preserved skeletal muscle oxidative capacity with aging after accounting for life span extension by CR, and determined if mitochondrial content, mitochondrial DNA integrity, and peroxisome proliferator-activated receptor gamma coactivator- 1a (PGC-1a) were involved. Ad libitum-fed (AL) and CR animals representing young adult, late middle age, and senescence were studied. Whereas citrate synthase and complex
Cell Metabolism, 2015
The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which... more The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which PA prevents disease and improves health outcomes are poorly understood. To identify major gaps in knowledge and potential strategies for catalyzing progress in the field, the NIH convened a workshop in late October 2014 entitled "Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits." Presentations and discussions emphasized the challenges imposed by the integrative and intermittent nature of PA, the tremendous discovery potential of applying…
PLoS ONE, 2014
PGC-1a regulates critical processes in muscle physiology, including mitochondrial biogenesis, lip... more PGC-1a regulates critical processes in muscle physiology, including mitochondrial biogenesis, lipid metabolism and angiogenesis. Furthermore, PGC-1a was suggested as an important regulator of fiber type determination. However, whether a muscle fiber type-specific PGC-1a content exists, whether PGC-1a content relates to basal levels of mitochondrial content, and whether such relationships are preserved between humans and classically used rodent models are all questions that have been either poorly addressed or never investigated. To address these issues, we investigated the fiber type-specific content of PGC-1a and its relationship to basal mitochondrial content in mouse, rat and human muscles using in situ immunolabeling and histochemical methods on muscle serial cross-sections. Whereas type IIa fibers exhibited the highest PGC-1a in all three species, other fiber types displayed a hierarchy of type IIx.I.IIb in mouse, type I = IIx. IIb in rat, and type IIx.I in human. In terms of mitochondrial content, we observed a hierarchy of IIa.IIx.I.IIb in mouse, IIa .I.IIx. IIb in rat, and I.IIa. IIx in human skeletal muscle. We also found in rat skeletal muscle that type I fibers displayed the highest capillarization followed by type IIa .IIx.IIb. Finally, we found in human skeletal muscle that type I fibers display the highest lipid content, followed by type IIa.IIx. Altogether, our results reveal that (i) the fiber type-specific PGC-1a and mitochondrial contents were only matched in mouse, (ii) the patterns of PGC-1a and mitochondrial contents observed in mice and rats do not correspond to that seen in humans in several respects, and (iii) the classical phenotypes thought to be regulated by PGC-1a do not vary exclusively as a function of PGC-1a content in rat and human muscles.
PLoS ONE, 2012
The aging heart is characterized by a progressive decline in contractile function and diastolic r... more The aging heart is characterized by a progressive decline in contractile function and diastolic relaxation. Amongst the factors implicated in these changes is a progressive replacement fibrosis secondary to cardiomyocyte death, oxidative damage, and energetic deficit, each of which may be secondary to impaired mitochondrial function. Here, we performed an in-depth examination of mitochondrial function in saponin-permeabilized cardiomyocyte bundles, a preparation where all mitochondria are represented and their structure intact, from young adult (YA) and senescent (SEN) rats (n = 8 per group). When accounting for increased fibrosis (+19%, P<0.01) and proportional decrease in citrate synthase activity in the SEN myocardium (-23%, P<0.05), mitochondrial respiration and reactive oxygen species (H(2)O(2)) emission across a range of energized states was similar between age groups. Accordingly, the abundance of electron transport chain proteins was also unchanged. Likewise, except for CuZnSOD (-37%, P<0.05), the activity of antioxidant enzymes was unaltered with aging. Although time to mitochondrial permeability transition pore (mPTP) opening was decreased (-25%, P<0.05) in the SEN heart, suggesting sensitization to apoptotic stimuli, this was not associated with a difference in apoptotic index measured by ELISA. Collectively, our results suggest that the function of existing cardiac ventricular mitochondria is relatively preserved in SEN rat heart when measured in permeabilized cells.
Engineering Structures, 2011
The senescent heart has decreased systolic and diastolic functions, both of which could be relate... more The senescent heart has decreased systolic and diastolic functions, both of which could be related to alterations in cardiac sarcoplasmic reticulum (SR) calcium (Ca2+) handling. The purpose of this study was to determine if SR protein content and rates of Ca2+ release and uptake and ATPase activity are lower in the senescent (34–36mo) Fisher 344×Brown-Norway F1 hybrid rat heart and
Medicine & Science in Sports & Exercise, 2010
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2004
Although mitochondrial DNA damage accumulates in aging skeletal muscles, how this relates to the ... more Although mitochondrial DNA damage accumulates in aging skeletal muscles, how this relates to the decline in muscle mass-specific skeletal muscle aerobic function is unknown. We used a pump-perfused rat hind-limb model to examine maximal aerobic performance ( _ VO 2max ) in young adult (YA; 8-9-month-old), late middle aged (LMA; 28-30-month-old) and senescent (SEN; 36month-old) Fischer 344 3 Brown Norway F1-hybrid rats at matched rates of convective O 2 delivery (QO 2 ). Despite similar muscle QO 2 during a 4-minute contraction bout, muscle massspecific _ VO 2max was reduced in LMA (15%) and SEN (52%) versus YA. In plantaris muscle homogenates, nested polymerase chain reaction revealed an increased frequency of mitochondrial DNA deletions in the older animals. A greater reduction in the flux through electron transport chain complexes I-III than citrate synthase activity in the older animals suggests mitochondrial dysfunction consequent to mitochondrial DNA damage with aging. These results support the hypothesis that a reduced oxidative capacity, due in part to age-related mitochondrial dysfunction, contributes to the decline in aerobic performance in aging skeletal muscles.
Experimental Gerontology, 2010
Age-related loss of muscle mass and function exhibits a marked acceleration from late middle age ... more Age-related loss of muscle mass and function exhibits a marked acceleration from late middle age to senescence and exercise training is one method that has been proposed to slow this process. The purpose of this study was to determine if long-term treadmill exercise training initiated at late middle age could increase endogenous antioxidant enzyme activity and attenuate the loss of skeletal muscle contractile properties in the gastrocnemius/plantaris (GAS/Plan) and soleus (SOL) muscles of senescent rats (34-36 mo) through a decrease in oxidative damage. Male Fisher 344 × Brown Norway F1-hybrid rats underwent 5-7 mo of treadmill training beginning at late middle age (29 mo). A 7 mo sedentary adult group was used to investigate age-related changes. Aging caused an increase in antioxidant enzyme activities; however, only SOD activity was further increased with exercise training. Exercise training did not attenuate the decrease in twitch or tetanic tension of the GAS/Plan or SOL. It did, however, prevent the increase in twitch half relaxation time of the SOL muscle only. Oxidative damage, as reflected in carbonyl content, was increased with age and even further with exercise training in the GAS muscle. Muscle fibre cross sectional area was decreased with age and even further with exercise training. Interestingly, small muscle fibres showed the highest accumulation of carbonyls. Overall, despite an augmentation of select antioxidant enzyme activities, exercise training from late middle age through to senescence had minimal benefits for muscle contractile properties, perhaps in part due to exacerbated oxidation.
Autophagy, 2013
autophagy is an important proteolytic pathway in skeletal muscles. The roles of muscle fiber type... more autophagy is an important proteolytic pathway in skeletal muscles. The roles of muscle fiber type composition and oxidative capacity remain unknown in relation to autophagy. The diaphragm (Dia) is a fast-twitch muscle fiber with high oxidative capacity, the tibialis anterior (Ta) muscle is a fast-twitch muscle fiber with low oxidative capacity, and the soleus muscle (sol) is a slow-twitch muscle with high oxidative capacity. We hypothesized that oxidative capacity is a major determinant of autophagy in skeletal muscles. Following acute (24 h) starvation of adult c57/Bl6 mice, each muscle was assessed for autophagy and compared with controls. autophagy was measured by monitoring autophagic flux following leupeptin (20 mg/kg) or colchicine (0.4 mg/kg/day) injection. oxidative capacity was measured by monitoring citrate synthase activity. in control mice, autophagic flux values were significantly greater in the Ta than in the Dia and sol. in acutely starved mice, autophagic flux increased, most markedly in the Ta, and several key autophagy-related genes were significantly induced. in both control and starved mice, there was a negative linear correlation of autophagic flux with citrate synthase activity. starvation significantly induced aMPK phosphorylation and inhibited aKT and rPs6KB1 phosphorylation, again most markedly in the Ta. starvation induced Foxo1, Foxo3 and Foxo4 expression and attenuated the phosphorylation of their gene products. We conclude that both basal and starvationinduced autophagic flux are greater in skeletal muscles with low oxidative capacity as compared with those with high oxidative capacity and that this difference is mediated through selective activation of the aMPK pathway and inhibition of the aKT-MTor pathways.
Aging Cell, 2010
Mitochondria regulate cellular bioenergetics and apoptosis and have been implicated in aging. How... more Mitochondria regulate cellular bioenergetics and apoptosis and have been implicated in aging. However, it remains unclear whether age-related loss of muscle mass, known as sarcopenia, is associated with abnormal mitochondrial function. Two technically different approaches have mainly been used to measure mitochondrial function: isolated mitochondria and permeabilized myofiber bundles, but the reliability of these measures in the context of sarcopenia has not been systematically assessed before. A key difference between these approaches is that contrary to isolated mitochondria, permeabilized bundles contain the totality of fiber mitochondria where normal mitochondrial morphology and intracellular interactions are preserved. Using the gastrocnemius muscle from young adult and senescent rats, we show marked effects of aging on three primary indices of mitochondrial function (respiration, H 2 O 2 emission, sensitivity of permeability transition pore to Ca 2+ ) when measured in isolated mitochondria, but to a much lesser degree when measured in permeabilized bundles. Our results clearly demonstrate that mitochondrial isolation procedures typically employed to study aged muscles expose functional impairments not seen in situ. We conclude that aging is associated with more modest changes in mitochondrial function in sarcopenic muscle than suggested previously from isolated organelle studies.