Kirsten R. Dunlap1, Megan E. Rosa-Caldwell1, Jacob L. Brown1, David E. Lee1, Wesley S. Haynie1, Richard A. Perry1, Lisa T. Jansen1, Seongkyun Lim1, Katarina A. Bejarano1, Michael P. Wiggs2, Tyrone A. Washington1, & Nicholas P. Greene1

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

Muscle atrophy is a significant pathology and major contributor to mortality across a variety of diseases. However, little is known regarding the etiology of the initiating events and progression of atrophy, demonstrating a critical need to understand cellular events promoting atrophy during pathological conditions. More so, the role of biological sex on cellular underpinnings of atrophy also remains unclear. Evidence from our laboratory suggests that a deterioration in mitochondrial quality in male mice is a precursor to cancer-induced muscle atrophy, however it is unknown if this is a conserved mechanism across other atrophic conditions, such as disuse. As such, studying mitochondrial quality alterations during the development of disuse atrophy, may provide basis for development of therapeutic interventions. PURPOSE: To evaluate mitochondrial quality during the progression of disuse atrophy between male and female mice. METHODS: Male and female C57BL/6J were transfected with pMitoTimer, a fluorescent reporter of mitochondrial quality, in the right flexor digitorum brevis at 6wks of age. After 2wks of recovery, animals were hindlimb unloaded for 0(CON), 24, 48, 72 or 168 hours to induce disuse atrophy. At designated time points, mice were humanely euthanized and tissues were collected for analysis of mitochondrial quality by pMitoTimer. Data within sex were analyzed via one-way ANOVA with Tukey post-hoc, α set at 0.05. Pairwise contrasts were used to analyze data between sex at each time point, α set at 0.01. RESULTS: Gastrocnemius weight was significantly lower at 48 hours in males (12%) and at 24 hours in females (7%) compared to same sex control (p<0.05). Significantly greater pMitoTimer red/green ratios were observed at 24 hours in males (62%) and at 168 hours in females (37%) compared to same sex control (p<0.05) indicative of mitochondrial network degeneration at these time points. CONCLUSION: Mitochondrial network degeneration preceded disuse-induced atrophy in male mice. However, in female mice degeneration of the mitochondrial network is not apparent until well after onset of muscle wasting. Our data suggest divergent deterioration of the mitochondrial network between biological sexes during disuse atrophy.

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

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