Article Title



Megan Rosa-Caldwell1, Wesley Haynie1, Kirsten Dunlap1, Seongkyun Lim1, Lisa Jansen1, Jacob Brown1, David Lee1, Katarina Bejarano1, Tyrone Washington1, Michael Wiggs2, Nicholas Greene1.

1University of Arkansas, Fayetteville, AR; 2University of Texas at Tyler, Tyler, TX

Muscle atrophy is a concurrent pathology among a variety of diseases and a significant predictor of mortality and quality of life. Clinically, these pathologies present differently between males and females, however mechanisms for these differences remain unclear. Mitochondrial health may be a mediator of muscle size and a possible mechanism for sexual dimorphisms during atrophic conditions. PURPOSE: To investigate sex differences in mitochondrial turnover (including: biogenesis, content, and mitophagy) during the progression of disuse-induced muscle atrophy. METHODS: 100 C57BL/6J mice were hindlimb unloaded to induce disuse muscle atrophy for 0(con), 24, 48, 72, or 168 hrs. At designated time points, tissues were collected for mRNA analysis of mitochondrial biogenesis, content and mitophagy markers in gastrocnemius muscle, and histological assessment of fluorescently-tagged degenerated mitochondria in flexor digitorum brevis. Within sex data were analyzed by one-way ANOVA with a Tukey post hoc. Pre-planned pairwise contrasts were used to determine differences between sexes at each time point. RESULTS: Female mice had 10% loss in body weight and 7-10% loss of soleus and gastrocnemius weight at 24hrs (p<0.05), whereas males did not experience weight loss until the 48hrs time point, losing ~10% of body, gastrocnemius, and soleus weight (p<0.05). Content of mitochondrial biogenesis regulator Pgc1α1 was 28% lower at 24hrs in males(p<0.05), whereas females had no alterations in Pgc1α1. Mitochondrial content, measured by Cox4, did not differ across time points or between sexes during the progression of disuse (p>0.05). Mitophagy marker Bnip3, demonstrated a sexually divergent response, with females having 200-300% more Bnip3 at 48hrs and 72hrs of disuse (p<0.05), whereas males did not statically differ from within sex controls (p>0.05). Content of degenerated mitochondria was ~2 fold greater in males compared to females at 24hrs, 48hrs, and 168hrs of disuse (p<0.01). CONCLUSION: Disuse atrophy differentially affects mitochondrial turnover between sexes during development of muscle wasting and may underlie wasting mechanisms contributing to divergent clinical manifestations of atrophy.

ACKNOWLEDGEMENTS: This study was funded by the National Institutes of Health, Award number: R15 AR069913/AR/NIAMS.

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