Exploiting metabolic and molecular alterations as therapeutic targets for skeletal muscle atrophy in inflammatory diseases

Skeletal muscle atrophy is one of the main features of cachexia, a complex multi-organ disease associated with cancer, sepsis, and other chronic conditions marked by systemic inflammation. Despite its high prevalence and significant impact on patients' quality of life and therapeutic outcomes, cachexia remains an unmet medical need, as its underlying mechanisms are not fully understood. This study focuses on uncovering novel mechanisms driving skeletal muscle atrophy to identify novel potential therapeutic targets. Starting during the SARS-CoV-2 pandemic, our research initially centered on patients in Intensive Care Units (ICUs) undergoing invasive mechanical ventilation (IMV). These patients, especially those suffering from systemic inflammation due to COVID-19, sepsis, or pneumonia, were found to be at high risk for severe skeletal muscle atrophy. We found that their plasma induced skeletal muscle wasting, oxidative stress, and mitochondrial dysfunction in vitro, highlighting the central role of inflammatory cytokines in muscle catabolism. Notably, extracellular vesicles (EVs) reversed muscle atrophy and mitigate oxidative stress, suggesting their potential as therapeutic agents for sepsis-induced muscle wasting. We then investigated the mechanisms behind mitochondrial dysfunction in cancer-induced skeletal muscle atrophy. Our findings revealed that alterations in systemic iron metabolism led to abnormal iron compartmentalization within atrophic muscle fibers, further exacerbating mitochondrial dysfunction. Iron supplementation not only preserved muscle function and prolonged survival in cachectic mice, but also restored muscle strength in anemic cancer patients. These results emphasize the critical role of iron homeostasis in maintaining muscle mass and function, suggesting that targeting iron metabolism could offer a therapeutic strategy for cancer cachexia. Subsequently, intrigued by the upregulation of the iron-regulating hormone erythroferrone (ERFE) in cachexia, known to inhibit BMP signaling in the liver, we identified and characterized two novel BMP inhibitors involved in skeletal muscle atrophy: the BMP scavenger ERFE and the intracellular inhibitor FKBP12. To overcome the BMP resistance mediated by these inhibitors, we administered low-dose tacrolimus (FK506) to target FKBP12. FK506 effectively restored BMP signaling, preventing skeletal muscle wasting in vitro and in vivo while also protecting against neuromuscular junction disruption and force loss. We therefore proposed that low-dose FK506 may represent a promising therapeutic approach for restoring BMP signaling in atrophic skeletal muscles, thereby offering a potential treatment for cancer cachexia.