Considering sexually dimorphic responses to aerobic exercise in treating glucocorticoid‐induced myopathy

Glucocorticoids are a class of steroid hormones with its primary function being to mitigate systemic inflammatory signals. Due to these functions, exogenous glucocorticoids, like dexamethasone (DEX), are commonly prescribed to treat inflammation in conditions such as ageing and cancer. However, chronic glucocorticoid use can also result in muscle degradation and weakness, resulting in conditions leading to myopathy. Laskin et al. (2024) investigated the effects of aerobic exercise on glucocorticoid-induced myopathy in aged mice. The authors found several key findings, including that DEX treatment induced sex-specific changes in skeletal muscle related to contractile properties, particularly in aged female mice. Moreover, aerobic exercise prevented fatigue in DEX-treated females, but not in males. Additionally, aerobic exercise promoted mitochondrial quality control mechanisms, including increased anti-apoptotic proteins, which may counteract glucocorticoid-induced mitochondrial stress. Due to the ubiquity of glucocorticoid usage, mitigating the skeletal muscle wasting that occurs following administration is critical for improving their utility in a clinical setting. Sarcopenia is characterized by the loss of skeletal muscle mass and strength in ageing populations. Exercise has been demonstrated to mitigate the effects of sarcopenia through various pathways. Barel et al. (2010) conducted a similar study to Laskin et al. (2024), whereby male Wistar rats (7–8 weeks old) underwent an 8-week aerobic exercise protocol and DEX treatment. The exercise protocol was individualized to each rat, whereby they ran at 60% of their predetermined maximal effort for one hour, 5 days a week. Halfway through the study, a second maximal test was conducted and speed was altered. This is different from Laskin et al. (2024) where the mice were subjected to an exercise routine at approximately 75−80% of their VO2 max for 30 min. Barel et al. (2010) found that exercise did not protect against loss of body weight. Although exercise did not fully protect against this decrease, trained rats did not decrease as much as sedentary rats. Laskin et al. (2024) revealed that while exercise did not always significantly increase muscle mass, it did preserve the mass of the triceps surae and gastrocnemius muscles in both male and female mice when comparing the percentage differences between DEX-treated groups in both males and females which shows that exercise may protect against the loss of skeletal muscle. Glucocorticoids are sometimes prescribed for patients with cancer to reduce systemic inflammation and improve cancer-associated anorexia. However, due to the myopathic effects of these drugs, an area of concern is that they would further the cancer-induced loss of skeletal muscle termed cancer cachexia (CCx). CCx is currently unable to be treated with nutritional or pharmacological interventions but exercise has been shown to be efficacious in maintaining skeletal muscle mass, at least in patients that can tolerate it. This work by Laskin et al. (2024) aimed to examine the effect of DEX treatment on skeletal muscle atrophy in aged mice. An interesting finding of this study was that DEX treatment impacts females to a greater degree than males, with a significant interaction of sex differences and exercise. Additionally, it was demonstrated that submaximal aerobic exercise was able to attenuate glucocorticoid-induced atrophy in the female gastrocnemius, but not in the male. It can be concluded that exercise modulates the response to glucocorticoid treatment in aged skeletal muscle in a sex-specific manner (Laskin et al., 2024). Martin et al. (2022) examined the levels of both endogenous glucocorticoids and glucocorticoid-induced gene expression in multiple models of CCx. This report revealed that the expression of glucocorticoid-responsive genes was upregulated in conjunction with an increase in glucocorticoid levels in both the circulation and the quadriceps across all tested mouse models. Additionally, these increases were observed to be age-dependent (Martin et al., 2022). Of relevance, FoxO1, which acts synergistically with the glucocorticoid receptor to induce E3 ligase expression and induce skeletal muscle atrophy, was found to be upregulated (Martin et al., 2022). These data support the proposition that elevations in endogenous glucocorticoids present throughout the progression of CCx and influence ageing skeletal muscle. The work by Laskin and colleagues supports the suggestion that females may benefit to a greater extent than males from aerobic exercise in mediating CCx. Future work should uncover whether submaximal aerobic exercise reduces skeletal muscle wasting in CCx through blunting glucocorticoid signalling. The study by Laskin et al. (2024) provided critical insights into myopathy and sex differences in aged muscle. Ultimately, Laskin et al. (2024) revealed that following DEX treatment there is a sexually dimorphic response to glucocorticoids in aged muscle, with aerobic exercise reducing fatigue in females but not in males. The authors concluded the article by posing questions; one of which asked why glucocorticoids elicit sexually dimorphic responses in sub-tetanic contractile properties. Laskin et al. (2024) mention that the exact mechanisms for this are still unknown, but the multifactorial design used for this study makes the data compelling to see sex differences. While using an aged mouse model is an effective design that demonstrates glucocorticoid myopathy, translating this research design to humans may be difficult. Sex hormones typically decrease in both males and females (via andropause and menopause), and the decline of these hormones is linked to the loss of muscular function and muscle mass. Testosterone is known to prevent the DEX-induced atrophy of skeletal muscle by blocking the expression of the FoxO1 gene, while oestrogen has been shown to induce Akt phosphorylation in myoblasts (Kim et al., 2016). As such, a decrease in muscle Akt phosphorylation due to a decline in oestrogens (e.g. following menopause) could cause a decline in muscle mass. While the role of sex hormones in muscle mass, function and sarcopenia in aged muscle is well established, their mechanistic role in glucocorticoid-induced myopathy remains unclear. Some research has been conducted on the effects of testosterone, but its relationship with female sex hormones (i.e. oestrogens and progesterone) are still not fully understood (Kim et al., 2016). The study by Laskin et al. (2024) has paved the way for future research on ageing with respect to sex differences, particularly the interaction between female sex hormones and glucocorticoids. Ultimately, they highlight that female sex hormones could be playing a role in increasing sub-tetanic force production and faster rates of force development in response to glucocorticoid treatment. This line of inquiry could significantly contribute to our understanding of muscle health and potentially reduce the prevalence of glucocorticoid-induced myopathy. The work by Laskin et al. (2024) offers valuable insights into the potential role of mitochondrial quality control, particularly mitophagy, in aged mice treated with DEX during rest and exercise. Findings from this study showing the expression of mitophagy-related proteins, notably PRKN and BNIP3, provide valuable insights into alterations in mitophagic signalling under various conditions. Notably, the behaviour of these proteins differs significantly; PRKN showed sex-specific responses to exercise yet no response to DEX, while BNIP3 showed considerable variability in its expression, including different exercise intensities, sex differences and DEX treatment. This observation is intriguing as it suggests a potentially unique role for BNIP3 in the regulation of mitophagy within muscle tissues, which is supported by previous work in myoblast cultures (Baechler et al., 2019). Furthermore, the study raises intriguing possibilities for future research directions that could enhance our understanding of mitophagic processes. For instance, incorporating additional autophagy cargo recognition molecules such as LC3 and SQSTM1 in the analysis could provide a more comprehensive view of autophagic activity. Additionally, the suggestion to perform mitochondrial fractionation to assess the precise localization of these proteins is particularly compelling. Such investigations could clarify whether these proteins are actively targeting mitochondria, which is needed for mitophagy. This approach could significantly refine our understanding of the molecular mechanisms underpinning mitophagy in response to physiological stresses like exercise and pharmacological interventions such as DEX treatment. The investigation of glucocorticoids as a causative factor of myopathy is important for both aged and diseased populations. While their exogenous use is often necessary, understanding the mechanisms of myopathy is necessary for the implementation of correct intervention. The work done by Laskin and colleagues explores this phenomenon in an aged mouse model, specifically investigating the usage of aerobic exercise as a short-term protective measure for DEX-induced myopathy. The utilization of an aged model is crucial due to the presence of age-related sarcopenia, which possibly factors into myopathic outcomes. These findings may translate to disease states in which myopathy is also present, such as CCx. Their work yielded significant sexual dimorphisms in the mechanisms of glucocorticoid signalling and receptor function, indicating hormonal influence. These data were further reinforced by the examination of mitochondrial function as a potential factor. Together, Laskin et al. (2024) have generated an important piece of research in not only understanding, but guiding the field towards developing an interventional model for those who cannot afford glucocorticoid-induced myopathy. There are no conflicts of interest to declare. All authors wrote, edited, and revised the final document. F.A.R. is supported by a NSERC Canadian Graduate Scholarship. The authors would like to thank Dr Matthew Krause for his valuable insights and reading of the final document.

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