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Article Title

SEX DIFFERENCES IN ANABOLIC REGULATORS DURING DEVELOPMENT OF ATROPHIC PATHOLOGY IN HINDLIMB UNLOADING-INDUCED DISUSE

Abstract

1Lisa T. Jansen, 1Megan E. Rosa-Caldwell, 1Wesley S. Haynie, 1Seongkyun Lim,

1Kirsten R. Dunlap, 1Jacob L. Brown, 1David E. Lee, 1Richard A. Perry 2Michael P. Wiggs, 1Tyrone A. Washington, 1Nicholas P. Greene, FACSM

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

Muscle atrophy is a comorbidity in many disease conditions, contributing to accelerated disease progression/terminal outcomes. Muscle wasting results from uncoordinated protein synthesis and protein degradation, as either decreased protein synthesis or increased protein degradation yield reductions in muscle mass and functionality. Atrophic conditions differentially affect discrete muscle types. For many diseases, onset and progression of muscle atrophy presents differently between sexes; yet, most research has focused on muscle wasting pathologies in males alone; thus, data on gender differences in anabolic regulatory gene responses following atrophic stimuli are sparse. While Deptor is a regulator of mTOR/protein synthetic activity, Pgc-14 and IGF-1 have been identified as key mediators in myocyte growth. PURPOSE: To assess gene content outcomes of anabolic regulators Pgc-14, IGF-1, and Deptor, in female and male mice during initiation and progression of disuse atrophy across multiple fiber types. METHODS: 100 female and male C57BL/6J mice were hindlimb unloaded for 0h, 24h, 48, 72 and 168h, to induce muscle atrophy. At assigned endpoints, soleus and gastrocnemius muscles were excised and processed for mRNA analysis of Pgc-14, IGF-1, and Deptor using RT-PCR. Data were analyzed by one-way ANOVA within each sex, . Pre-planned contrast comparisons determined sex differences at each time point. RESULTS: Soleus and gastrocnemius masses presented lower at 24h in female (-11.8%, -9%; p<0.05) and 48h in male (-16%, -13%; p<0.05) compared to control. In soleus, mRNA content of Pgc-14 declined over time in females, while spiking >9, >6-fold in males at 72h and 168h (p<0.05). In contrast, IGF-1 showed higher content in females at 72h and 168h (+77%, +27%; p<0.05) than males. In gastrocnemius, Pgc-14 content spiked >3-fold in females at 24h (p<0.05). Female IGF-1 content was significantly elevated compared to male at 72h (p<0.05). Deptor content in gastrocnemius was >3-fold from baseline at 24h in females and >2-fold from baseline at 48h in males (p<0.05). CONCLUSION: Anabolic regulator responses to atrophic stimuli differ across sex, muscle tissue and time course of muscle atrophy. These early findings could suggest Deptor as a novel therapeutic target to ameliorate muscle wasting conditions.

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

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