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.
Mitochondria are fascinating organelles regulating many critical cellular processes for skeletal muscle physiology. They play central roles in muscle cell metabolism, energy supply,
regulation of energy-sensitive signalling pathways, reactive oxygen species production/signalling, calcium homeostasis and the regulation of apoptosis.
Given these multifaceted roles of mitochondria in fundamental aspects of muscle cell physiology, it is not surprising that mitochondrial dysfunction has been
implicated in a large number of adverse conditions affecting skeletal muscle health. This includes for instance the aging-related loss of muscle mass and function,
disuse-induced muscle atrophy, ventilator-induced diaphragmatic dysfunction, Duchenne and collagen muscular dystrophies, long-term muscle dysfunction induced
by chemotherapy treatment, sepsis-induced muscle wasting and the development of insulin resistance.
Maintaining optimal mitochondrial content and function, or in other words mitochondrial fitness, is therefore critical for skeletal muscle cells.
The maintenance of mitochondrial fitness relies on the subtle coordination of processes involved in mitochondrial biogenesis, mitochondrial dynamics
(fusion and fission processes shaping mitochondrial morphology), and mitochondrial quality control processes such as mitophagy (a process in charge of the removal of dysfunctional mitochondria).
While the role played by mitochondrial biogenesis and function has received intense research effort, very little is known about the roles that mitochondrial dynamics and mitophagy
plays in skeletal muscle health. Defining the mechanisms regulating these novel aspects of mitochondrial biology, as well as the interrelationships existing between mitochondrial function,
dynamics and mitophagy will be critical to increase our understanding of the role played by mitochondria in normal skeletal muscle function and their implications in muscle dysfunction/diseases.
This knowledge will also be essential for the development and the optimisation of therapeutic strategies for the treatment of a host of diseases or adverse conditions affecting skeletal muscles
and their mitochondria.
The overall aim of our research program is to uncover the roles that mitochondrial dynamics and mitophagy play in skeletal muscle health and aging.
This research program is organized around the 3 following axes:
Investigating interrelations between mitochondrial function, morphology, dynamics (fusion and fission) and mitophagy
(removal of dysfunctional mitochondria) in skeletal muscles.
Defining the role of mitochondrial dynamics and mitophagy in muscle health and plasticity.
Uncovering the roles played by mitochondrial dynamics and mitophagy in the muscle aging-process.
Our most important contributions
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.