Female mice may have exacerbated catabolic signalling response compared to male mice during development and progression of disuse atrophy

Abstract

Background Muscle atrophy is a common pathology associated with disuse, such as prolonged bed rest or spaceflight, and is associated with detrimental health outcomes. There is emerging evidence that disuse atrophy may differentially affect males and females. Cellular mechanisms contributing to the development and progression of disuse remain elusive, particularly protein turnover cascades. The purpose of this study was to investigate the initial development and progression of disuse muscle atrophy in male and female mice using the well‐established model of hindlimb unloading (HU). Methods One hundred C57BL/6J mice (50 male and 50 female) were hindlimb suspended for 0 (control), 24, 48, 72, or 168 h to induce disuse atrophy (10 animals per group). At designated time points, animals were euthanized, and tissues (extensor digitorum longus, gastrocnemius, and soleus for mRNA analysis, gastrocnemius and extensor digitorum longus for protein synthesis rates, and tibialis anterior for histology) were collected for analysis of protein turnover mechanisms (protein anabolism and catabolism). Results Both males and females lost ~30% of tibialis anterior cross‐sectional area after 168 h of disuse. Males had no statistical difference in MHCIIB fibre area, whereas unloaded females had ~33% lower MHCIIB cross‐sectional area by 168 h of unloading. Both males and females had lower fractional protein synthesis rates (FSRs) within 24–48 h of HU, and females appeared to have a greater reduction compared with males within 24 h of HU (~23% lower FSRs in males vs. 40% lower FSRs in females). Males and females exhibited differential patterns and responses in multiple markers of protein anabolism, catabolism, and myogenic capacity during the development and progression of disuse atrophy. Specifically, females had greater mRNA inductions of catabolic factors Ubc and Gadd45a (~4‐fold greater content in females compared with ~2‐fold greater content in males) and greater inductions of anabolic inhibitors Redd1 and Deptor with disuse across multiple muscle tissues exhibiting different fibre phenotypes. Conclusions These results suggest that the aetiology of disuse muscle atrophy is more complicated and nuanced than previously thought, with different responses based on muscle phenotypes and between males and females, with females having greater inductions of atrophic markers early in the development of disuse atrophy.

Mitochondrial aberrations during the progression of disuse atrophy differentially affect male and female mice

“…At 8 weeks of age animals underwent electroporation of the flexor digitorum brevis muscle with pMitoTimer as previously described 16 and is described more thoroughly in Data S1. After 2 weeks of recovery, disuse atrophy was induced using the hindlimb unloading model 10 . After 0–168 h of unloading, animals were euthanized and tissues collected.…”

“…Because of differential response to disuse across different muscle phenotypes, 18 we investigated mitochondrial aberrations across multiple muscle phenotypes including extensor digitorum longus (EDL, glycolytic muscle), gastrocnemius (mixed muscle), and soleus (oxidative muscle). A thorough description of hindlimb unloading and animal protocols can be found in our previous study using these same animals 10 as well as Data S1.…”

“…A one‐way ANOVA with Tukey post‐hoc test was used within each biological sex with factor levels including hours of disuse (0, 24, 48, 72, or 168 h). Additionally, to determine how outcome variables are altered during the progression of disuse we utilized trend analysis as we have previously published and described 10 . This analysis was used to determine overall patterns of the data that may not reach pairwise statistical significance and indirectly compare differential progressions of disuse atrophy in male and female mice.…”

“…Yet, preclinical models establishing mechanistic differences between male and female patients during muscle pathologies are limited, which limits the ability to develop therapeutics to mitigate muscle pathologies. Our recent work was the first to demonstrate biological sex differences in moderators of protein turnover between male and female patients during the early phases of disuse atrophy, 10 although there are likely other mechanisms contributing to these sex‐related differences.…”

Blocking ActRIIB signaling and restoring appetite reverses cachexia and improves survival in mice with lung cancer

“…There are known differences in body composition, EE, and peripheral organ metabolism between men and women . Gender discrepancies have also been observed in animal models of disuse atrophy and cardiac cachexia [65][66][67] . Additional studies are required to 3 identify the key pathophysiologic differences that drive the differential therapeutic 4 response between male and female KL mice.…”