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

Abstract

Background Disuse decreases muscle size and is predictive of mortality across multiple pathologies. Detriments to mitochondrial function are hypothesized to underlie disuse‐induced muscle atrophy. Little data exist on early mechanisms contributing to onset of these pathologies, nor is it known how they differ between sexes. The purpose of this study was to examine differential and conserved responses to mitochondrial quality control in male and female mice during the development and progression of disuse‐induced atrophy. Methods One hundred C57BL/6J mice (50 male and 50 female) were hindlimb unloaded to induce disuse atrophy for 0 (con), 24, 48, 72, or 168 h. At designated time‐points, extensor digitorum longus, gastrocnemius, and soleus muscles were collected for analysis of mitochondrial quality control markers. Results One hundred sixty‐eight hours of disuse resulted in ~25% lower oxidative muscle fibre CSA in both male (P = 0.003) and female (P = 0.02) mice without any differences due to disuse in glycolytic fibres. In male mice, 48 h of unloading was sufficient to result in ~67% greater mitochondrial oxidative stress as assessed by the reporter gene pMitoTimer compared with 0 h (P = 0.002), this mitochondrial stress preceded detectable muscle loss. However in female mice, mitochondrial oxidative stress did not occur until 168 h of disuse (~40% greater mitochondrial oxidative stress in 168 h compared with 0 h of disuse, P < 0.0001). Blunted oxidative stress in female mice appeared to coincide with greater inductions of autophagy and mitophagy in female mice (~3‐fold greater BNIP3 and ~6‐fold greater LC3II/I ratio P < 0.0001 and P = 0.038 respectively). Male mice overall had greater reactive oxygen species (ROS) production compared with female mice. Female mice had a greater induction of ROS within 24 h of disuse (~4‐fold greater compared with 0 h, P < 0.0001); whereas male mice did not have greater ROS production until 168 h of disuse (~2‐fold greater, P < 0.0001). Although all muscle types exhibited some alterations to mitochondrial quality control, such as increased markers of mitophagy and fission, the soleus muscle in both male and female mice exhibited consistent alterations to various markers of mitochondrial quality. Markers of mitochondrial translation were approximately 30–50% lower within 24 h of unloading in both male and female soleus muscle (P value ranges: <0.0001–0.03). Conclusions Disuse negatively affects mitochondria differentially between sexes during development of muscle wasting. Acutely, female mice may forgo muscle mass to maintain mitochondrial quality compared with male mice. These differences may contribute to divergent clinical manifestations of atrophy.

Increasing plasma L-kynurenine impairs mitochondrial oxidative phosphorylation prior to the development of atrophy in murine skeletal muscle: A pilot study

“…It is possible that a longer dietary L-Kyn intervention could result in atrophy or that mitochondrial abnormalities precede atrophy in muscle. The latter statement is supported by a recent study showing that mitochondrial degeneration occurs before muscle atrophy in male, but not female, mice subjected to disuse atrophy (Rosa-Caldwell et al, 2021). Although the mechanisms underlying mitochondrial OXPHOS deficits driven by L-Kyn are unknown, previous studies have documented that L-Kyn has direct inhibitory effects on some mitochondrial enzymes (Baran Frontiers in Physiology frontiersin.org et al, 2003;Thome et al, 2019).…”

“…In contrast to their results, the present study did not find any changes in muscle weights, myofiber size, or contractile function. The underlying reasons for this discrepancy are unclear, but one potential contributing factor is the difference in the sex of rodents used between the studies (Rosa-Caldwell et al, 2021). Further, the study by Kaiser et al did not report serum or plasma L-Kyn levels so it is not possible to compare the levels of L-Kyn between these studies.…”

The Time-Course of Cancer Cachexia Onset Reveals Biphasic Transcriptional Disruptions in Female Skeletal Muscle Distinct from Males

“…We previously documented impaired mitochondrial health in multiple atrophy models, including LLC-induced cachexia (17, 19, 22, 37). Specifically, mitochondrial degeneration preceded atrophy in male mice undergoing either LLC-induced cachexia or disuse atrophy, while females largely protect mitochondrial health until onset of muscle atrophy (17, 19).…”

PGC-1α overexpression is not sufficient to mitigate cancer cachexia in either male or female mice

“…Likewise, most preclinical studies in CC are focused on males, not accounting for phenotypical disparities between biological sexes reported in multiple human cancer types, such as lung cancer (Cosper and Leinwand 2011). Previous studies from our laboratory indicate differences in biological sex in several distinct muscle atrophy models (Brown et al 2017b(Brown et al , 2018Lim et al 2020Lim et al , 2022Rosa-Caldwell et al 2021). In fact, males appear to be more so affected by inflammation-induced muscle atrophy models than females, such as cancer-induced atrophy, whereby females concomitantly display lower ubiquitinproteasome activity when compared with males during CC Appl.…”