Increasing Mitochondrial Content Does Not Protect Against Disuse-induced Muscle Atrophy

Abstract

Skeletal muscle mass is maintained by a balance in protein synthetic and degradative pathways. Deteriorations to skeletal muscle health can have significant implications for whole body health and quality of life. This is particularly true for disuse-associated muscle wasting, a common pathology associated with ICU stays, casting and space flight. Mitochondrial aberrations have been hypothesized to underlie these muscle pathologies, as such; improving mitochondrial content is an enticing therapeutic target. PURPOSE: To investigate the sufficiency of increased mitochondrial content on mitigating disuse-induced muscle atrophy. METHODS: Mice overexpressing muscle PGC-1α (PGC-1α) and WT mice were bred at the University of Arkansas. At 10 wks of age, male and female mice (~8-10/group, ~70 mice total) underwent hindlimb unloading (HU) or normal cage activity (CON) for 7 days. Tissues were then collected, weighed and prepared for mRNA analysis of mediators of proteasomal degradation. Data for males and females were analyzed by 2X2 ANOVA with a Tukey post-hoc. RESULTS: In both male and female mice, overexpression of PGC-1α was not sufficient to protect gastrocnemius, tibialis anterior, or soleus muscle atrophy (~17%, ~13%, ~27% lower muscle weights, respectively). In the gastrocnemius, MuRF-1 mRNA content was ~2.5-fold greater in male and female WT-HU mice compared to WT-CON; however, both male and female PGC-1α mice had ~40% less MuRF-1 content compared to WT-CON, regardless of intervention. Correspondingly, Atrogin1 mRNA content in the gastrocnemius was ~4-fold greater in male and female WT-HU mice compared to WT-CON; whereas both male and female PGC-1α mice had no differences in Atrogin1 content compared to WT-CON regardless of intervention. CONCLUSION: Although increased mitochondrial content appears to blunt the induction of the ubiquitin proteasomal degradation system during disuse atrophy, these blunted responses do not appear sufficient to mitigate disuse-induced muscle loss. This study was funded by the National Institutes of Health, Award number: R15 AR069913/AR/NIAMS