{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMyostatin (MSTN), also known as growth‐differentiation factor‑8, is a member of the transforming growth factor‑β superfamily that exerts a potent negative regulation on skeletal (and cardiac) muscle mass. It is initially synthesized as an inactive precursor that is secreted into the circulation in a latent complex; binding partners such as its propeptide, follistatin‑related proteins, WFIKKN1/2 and latent TGF‑β–binding proteins control its activation and bioavailability. Furthermore, extracellular conversion by proprotein convertases represents a critical regulatory step in its activation within muscle tissue."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMSTN expression is highly dynamic and responsive to the organism’s physiological status. Acute anabolic stimuli such as resistance exercise and essential amino acid ingestion have been shown to suppress MSTN mRNA and protein levels, thereby favoring muscle hypertrophy. In contrast, in various conditions characterized by muscle atrophy and wasting—including aging‐associated sarcopenia, hyperammonemia in cirrhosis, chronic heart failure, and even environmental insults like smoking—MSTN levels are elevated and contribute to impaired myoblast proliferation, differentiation, and enhanced protein degradation through both canonical Smad and noncanonical p38 MAPK (as well as Notch and Wnt) signaling pathways. These findings underscore MSTN’s pivotal role in coupling external stimuli to the regulation of muscle mass."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in myogenesis, genetic variants within the MSTN locus and its downstream signaling network are increasingly implicated in inter‐individual differences in muscle performance and adaptations to training. In parallel, targeted inhibition of MSTN—whether by antibodies, modified follistatin derivatives or by modulating its proteolytic activation—has shown promise in preclinical models for enhancing muscle mass, improving insulin sensitivity, favorably influencing bone remodeling, and even mitigating features of neuromuscular disorders. Collectively, these diverse studies support MSTN as not only a critical regulator of muscle homeostasis but also a compelling therapeutic target with broader metabolic and systemic implications."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOverall, the broad spectrum of research—spanning genetic analyses, animal models, and clinical investigations—reinforces MSTN’s multifaceted roles in muscle regulation, its contribution to pathological atrophy under diverse conditions (including chronic diseases, disuse and metabolic syndromes), and its complex interplay with inflammatory, endocrine, and apoptotic cascades that affect cardiac function, bone homeostasis, and regenerative capacity. This collection of studies provides a comprehensive framework for future therapeutic strategies aimed at modulating MSTN activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "29"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_fs", "start_ref": "30", "end_ref": "43"}, {"type": "fg_f", "ref": "24"}, {"type": "fg_f", "ref": "44"}, {"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jennifer J Hill, Monique V Davies, Adele A Pearson, et al. 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