WELCOME TO THE MUSCLE MITOCHONDRIA LABORATORY

| Ongoing Research | | Our Discoveries |

Overview of our research interest and activity

Skeletal muscles make up to 40/50% of the body mass of non-obese individuals, making them the largest type of tissue of the human body. While their importance is well recognized in the athletic field, their significance for general health is often underappreciated. Indeed, the evidence that muscle mass, strength and metabolism are essential for health is overwhelming. As the largest protein reservoir in the human body, muscles are essential in the acute response to critical illness such as sepsis, advanced cancer and traumatic injury. Loss of skeletal muscle mass as also been associated with weakness, fatigue, insulin resistance, falls, fear of falling, fractures, frailty, disability, a host chronic diseases and death. As a consequence, maintaining skeletal muscle mass, strength and metabolism throughout the lifespan is critical to the maintenance of whole body health.

The overall aim of our research program is to further our understanding of the mechanisms regulating muscle mass, health, plasticity and aging. To this end, we combine knowledge and expertise in physiology, cell biology, molecular biology, nutrition and exercise science. We study rodent models of muscle atrophy and hypertrophy and conduct studies in humans to investigate the mechanisms underlying muscle atrophy and weakness that develop during aging and disuse.

Our most important contributions

Cefis, Marcangeli et al. (2025), "Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men", Cell Reports Medicine: In this manuscript, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20–93. We report that physical activity partially protect against age-related decline in physical function. We show that mitochondrial respiration remains unaltered in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. We also report that mitochondrial reactive oxygen species production is unaffected by aging and higher in active participants. In contrast, we report data indicating that mitochondrial calcium retention capacity decreases with aging regardless of physical activity and correlates with muscle mass, performance, and the stress-responsive metabokine/mitokine GDF15. These findings indicate that targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.

Leduc-Gaudet et al. (2023), "MYTHO is a novel regulator of skeletal muscle autophagy and integrity", Nature Communications: In this manuscript, we identified and characterized a novel FoxO-dependent gene, which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuated muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression was sufficient to trigger muscle atrophy, MYTHO knockdown resulted in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown was associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuated the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) displayed reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. These data position MYTHO as a key regulator of muscle autophagy and integrity.

Dulac et al. (2020), "Drp1 knockdown induces severe muscle atrophy and remodelling, mitochondrial dysfunction, autophagy impairment and denervation", J Physiol: In this manuscript, we showed that knocking down Drp1 (a protein regulating mitochondrial fission) for 4 months in adult mouse skeletal muscle resulted in severe muscle atrophy (40-50%). Drp1 knockdown also led to a reduction in mitochondrial respiration, an increase in markers of impaired autophagy and increased muscle regeneration, denervation, fibrosis and oxidative stress. These data indicate that Drp1 is crucial for the maintenance of normal mitochondrial function and that Drp1 depletion severely impairs muscle health.

Leduc-Gaudet, Reynaud, et al. (2019), "Parkin overexpression protects from sarcopenia ", J Physiol: In this manuscript, we showed that parkin overexpression attenuates aging-related loss of muscle mass and strength and unexpectedly causes hypertrophy in adult skeletal muscles. We also show that Parkin overexpression leads to increases in mitochondrial content and enzymatic activities. Finally, our results show that Parkin overexpression protects from aging-related increases in markers of oxidative stress, fibrosis and apoptosis. Our findings therefore placed Parkin as a potential therapeutic target to attenuate sarcopenia and improve skeletal muscle health and performance.

Gouspillou G, et al. (2018), "Protective role of Parkin in skeletal muscle contractile and mitochondrial function", J Physiol: In this manuscript, we show that Parkin ablation causes a decrease in muscle specific force, a severe decrease in mitochondrial respiration, mitochondrial uncoupling and an increased susceptibility to opening of the permeability transition pore. These work demonstrated that Parkin plays a protective role in the maintenance of normal mitochondrial and contractile functions in skeletal muscles.

Gouspillou G, et al. (2014), "Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of Endonuclease G in atrophied muscle of physically active older humans", FASEB J: This work demonstrated that, in association with muscle fiber atrophy, mitochondria from healthy and active old men exhibit sensitized permeability transition pore (mPTP, a pore involved in the regulation of apoptosis) opening, mild uncoupling, without an increase in ROS production. It also showed that mitochondrial-mediated apoptosis is increased in aged human muscle. Finally, we gathered evidence suggesting that mitophagy is impaired in aged skeletal muscle, therefore providing a potential mechanism that could contribute to mitochondrial dysfunction and sarcopenia.

Gouspillou G, et al. (2014), "Mitochondrial energetics is impaired in vivo in aged skeletal muscle.", Aging Cell. In this work, we showed for the first time that the mitochondrial bioenergetics response to an increase in muscle energy demand was impaired in vivo in contracting rat muscle. We also showed in vitro that the underlying mechanism involved a decreased mitochondrial affinity for ADP.

Gouspillou G, et al. (2010) Alteration of mitochondrial oxidative phosphorylation in aged skeletal muscle involves modification of adenine nucleotide translocator (ANT), BBA Bioenergetics. In this manuscript, we evidenced that mitochondria isolated from aged muscle display an impaired regulation of their oxidative phosphorylation under low activities close to in vivo ATP turnover. We also provided strong evidence that this dysregulation of mitochondrial energetics was caused by changes in the ANT function.

Leduc-Gaudet JP et al. (2015) Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice. Oncotarget. Our lab evidenced that the aging-related decline in skeletal muscle mass and function is associated with an increase in the complexity in mitochondrial morphology and alterations in mitochondrial dynamics.

St-Jean-Pelletier F,et al. (2017). The impact of aging, physical activity and pre-frailty, on skeletal muscle phenotype, mitochondrial content and intramyocellular lipid in men, The Journal of Cachexia, Sarcopenia and Muscle. Our lab recently collected evidence indicating that aging in sedentary men is associated with (i) complex changes in muscle phenotype preferentially affecting type IIa fibres; (ii) a decline in mitochondrial content affecting all fiber types; and (iii) an increase in lipid content in type I fibres. Our results also suggest that physical activity partially protects from all of these effects of aging on skeletal muscle. Finally, we showed that mitochondrial content was positively correlated with clinically relevant markers of muscle function, functional capacities, and insulin sensitivity.