Biology subjects

Leduc-Gaudet, J.-P.

Publications and source records attributed to Leduc-Gaudet, J.-P..

3 recordsLinked to original sources

bioRxiv2025

Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but fails to improve key histological features in a mouse model of Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular disorder. Mitochondrial dysfunctions are key disease features of the disease, and strategies that improve mitochondrial health have emerged as promising to slow disease progression. Emerging evidence indicates that impaired/insufficient mitophagy may contribute to the accumulation of mitochondrial dysfunction seen in patients and animal models of DMD. We therefore hypothesized that overexpressing Parkin, a key mitophagy regulator, may improve mitochondrial and muscle health in a mouse model of DMD. To this end, Parkin was overexpressed using intramuscular injections of adeno-associated viruses performed in 5-week-old and 18-week-old D2.B10-Dmdmdx/J mice (D2.mdx), a widely used mouse model of DMD. Four and 16 weeks of Parkin overexpression initiated in 5-week-old and 18-week-old D2.mdx, respectively, resulted in muscle hypertrophy, as indicated by an increase in muscle mass and fiber cross-sectional area. While Parkin overexpression did not impact maximal mitochondrial respiration or mitochondrial content, it increased the Acceptor Control Ratio, an index of mitochondrial bioenergetic efficiency. Parkin overexpression also decreased mitochondrial H2O2 emission, a surrogate for mitochondrial ROS production. However, Parkin overexpression failed to reduce the proportion of fibers with central nuclei and markers of muscle damage and/or necrosis. Taken all together, our results indicate that Parkin overexpression can attenuate muscle atrophy, improve mitochondrial bioenergetics and lower mitochondrial ROS production in a mouse model of DMD. These findings showcase the partial beneficial effects of overexpressing Parkin in ameliorating some, but not all, pathological features observed in a mouse model of DMD. Graphical abstractImpact of AAV-mediated Parkin overexpression on Duchenne Muscular Dystrophy (DMD) progression in skeletal muscle of D2.mdx (a mouse model of DMD). Parkin overexpression attenuated muscle atrophy, reduced mitochondrial H2O2 emissions and improved an index of mitochondrial coupling efficiency. Created with BioRender.com. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/659533v3_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@143f08borg.highwire.dtl.DTLVardef@16543a9org.highwire.dtl.DTLVardef@13d1110org.highwire.dtl.DTLVardef@2b5e2e_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

Impact of physical activity on physical performance, mitochondrial bioenergetics, ROS production and calcium handling across the human adult lifespan

Aging-related muscle atrophy and weakness contribute to loss of mobility, falls and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence position physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status conferred partial protection against age-related decline in physical performance. A trend for reduced muscle mitochondrial respiration with aging was observed in inactive but not in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production was unaffected by aging and active participants displayed higher ROS production. In contrast, mitochondrial calcium retention capacity decreased with aging regardless of physical activity status and correlated with muscle mass, performance and the stress-responsive metabokine GDF15. Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.

cell biology↗

bioRxiv2021

Role of autophagy in sepsis-induced skeletal muscle dysfunction, whole-body metabolism, and survival

Septic patients frequently develop skeletal muscle wasting and weakness, resulting in severe clinical consequences and adverse outcomes. Autophagy is a stress-induced degradative process essential to cell survival. Recent studies have demonstrated that sepsis triggers sustained induction of autophagy in skeletal muscles, although the impact of this enhanced autophagy on sepsis-induced muscle dysfunction remains unclear. Atg7 is an autophagy gene that plays a major role in autophagosome formation. Using an inducible and muscle-specific Atg7 knockout mouse model (Atg7iSkM-KO), we investigated the functional importance of skeletal muscle autophagy in sepsis. Sepsis was induced using cecal ligation and perforation (CLP) with a sham operation serving as a control. Atg7iSkM-KO mice exhibited a more severe phenotype in response to sepsis, marked by severe muscle wasting and contractile dysfunction, hypoglycemia, higher ketone levels and a decreased in survival as compared to mice with intact Atg7. Several genes that encode 26S proteasome subunits were upregulated, suggesting that activation of the ubiquitin-proteasome system is responsible for the severe muscle atrophy that was seen in these mice. Sepsis and Atg7 deletion resulted in the accumulation of mitochondrial dysfunction, although sepsis did not further worsen mitochondrial dysfunction in Atg7iSkM-KO mice. Overall, our study demonstrates that autophagy inactivation in skeletal muscles triggers significant worsening of sepsis-induced contractile and metabolic dysfunctions and negatively impacts survival. Induction of autophagy in skeletal muscles in response to sepsis thus represents a protective mechanism.

cell biology↗