Skeletal Muscle Is a Hidden Endocrine Organ Driving Metabolic Health

For decades, skeletal muscle was viewed primarily as a mechanical organ. This comprehensive 2025 narrative review by Iglesias reframes muscle as a central endocrine player—both a target of classical hormones and a prolific source of signaling molecules—with profound implications for metabolic health and disease.

The review first examines muscle as a hormonal target. Anabolic hormones—GH, IGF-1, testosterone, and insulin—stimulate protein synthesis, satellite cell activation, and muscle hypertrophy via shared PI3K/Akt/mTOR signaling. IGF-1 also regulates mitochondrial biogenesis. Deficiencies in any of these hormones (GH deficiency, hypogonadism, insulin resistance) reduce lean mass and functional capacity. Catabolic mediators—glucocorticoids, catecholamines, myostatin, and proinflammatory cytokines—counteract anabolism through the ubiquitin-proteasome system, autophagy-lysosome pathways, and mTOR suppression, collectively driving muscle atrophy in pathological states like Cushing's syndrome, chronic illness, or prolonged corticosteroid use.

The second major theme is myokine biology. Skeletal muscle releases dozens of bioactive peptides during contraction. Key myokines discussed include: irisin (via FNDC5 cleavage), which promotes adipose tissue browning, improves insulin sensitivity, and may cross the blood-brain barrier; IL-6, which acts as both a pro- and anti-inflammatory signal depending on context; IL-15, which supports muscle hypertrophy and fat oxidation; BDNF, which links exercise to neuroprotection; myostatin, a potent negative regulator of muscle growth; FGF21, involved in lipid and glucose metabolism; SPARC, with anti-tumor and bone-metabolic roles; myonectin, regulating fatty acid uptake; LIF, supporting muscle repair; and Metrnl, a novel myokine mediating thermogenesis and immunometabolic modulation. Together, these molecules create an exercise-induced endocrine network that communicates with liver, adipose tissue, brain, pancreas, bone, and the cardiovascular system.

Myokine dysregulation is central to endocrine-metabolic disease. In obesity and type 2 diabetes, irisin and IL-6 levels are altered, GLUT4 translocation is impaired, and chronic low-grade inflammation disrupts myokine secretion patterns. Sarcopenia—loss of muscle mass and quality with aging or disease—compounds these deficits and worsens prognosis across endocrine conditions. The gut-muscle axis adds further complexity, with intestinal microbiota bidirectionally influencing muscle health and inflammatory tone.

Therapeutically, the review emphasizes that exercise remains the most potent stimulus for myokine secretion and muscle preservation. Hormone replacement (GH, testosterone) restores anabolic signaling in deficiency states. Anabolic agents show clinical promise but carry risks at supratherapeutic doses. Myokines themselves are positioned as next-generation biomarkers and pharmacological targets. The review advocates an integrative clinical approach that incorporates muscle biology into standard endocrinological care.