Myonectin

Myonectin (also known as CTRP15 or erythroferrone) is a secreted protein predominantly produced by skeletal muscle that functions as a myokine regulating systemic lipid metabolism, mitochondrial function, and tissue protection. The molecule belongs to the C1q/TNF-related protein (CTRP) family and forms disulfide-linked oligomers (trimers, hexamers, and higher-order structures) that are critical for its biological activity. PMID 22351773PMID 40741175PMID 32602701

Myonectin's primary biological functions include promoting fatty acid uptake in adipocytes and hepatocytes, reducing circulating free fatty acids, and protecting against ischemia-reperfusion injury in the heart. It upregulates genes involved in lipid uptake (CD36, FATP1, Fabp1, Fabp4) and activates key signaling pathways including sphingosine-1-phosphate (S1P)/cAMP/Akt and AMPK/PGC1α cascades. PMID 30566056PMID 22351773PMID 37542026 These pathways mediate anti-apoptotic, anti-inflammatory, and mitochondrial biogenesis effects across multiple tissues. PMID 30566056PMID 40741175PMID 37542026

Myonectin is considered an exerkine—specifically an exercise-induced myokine. This classification is supported by several lines of evidence: (1) voluntary exercise increases both its skeletal muscle expression and circulating levels; (2) treadmill exercise elevates circulating myonectin, and this elevation is necessary for exercise-mediated cardioprotection against ischemia-reperfusion injury; (3) myonectin is upregulated by compounds that raise cellular cAMP or calcium levels, mimicking exercise-induced muscle contraction; and (4) it is recognized in recent reviews as a canonical myokine that mediates inter-organ crosstalk in response to exercise. PMID 30566056PMID 31442362PMID 22351773PMID 40957493

Myonectin expression is tightly regulated by metabolic state—fasting suppresses while refeeding dramatically increases its levels—and it is downregulated in obesity. PMID 22351773PMID 40741175

Myonectin shows promise as a therapeutic target for skeletal muscle atrophy and dysfunction. In male mouse models, myonectin supplementation attenuated denervation-induced muscle atrophy through AMPK/PGC1α pathway activation, and treatment suppressed muscle atrophy in both senescence-accelerated mice and mdx mice (a model of Duchenne muscular dystrophy). PMID 37542026 These findings suggest potential applications in age-related sarcopenia and muscular dystrophies.

Cardiovascular protection represents another therapeutic avenue. Myonectin functions as an exercise-induced myokine that protects against myocardial ischemia-reperfusion injury by suppressing apoptosis and inflammation through S1P/cAMP/Akt-dependent signaling. PMID 30566056 Transgenic overexpression of myonectin in skeletal muscle reduced myocardial damage after ischemia-reperfusion in mice. PMID 30566056

The myokine also demonstrates metabolic regulatory potential. Myonectin regulates lipid uptake and distribution across tissues, reduces inflammation and apoptosis, and modulates mitochondrial function through AKT and AMPK-mediated pathways. PMID 40741175 It promotes fatty acid uptake in adipocytes and hepatocytes while reducing circulating free fatty acids, and inhibits adipogenesis through p38 MAPK pathway regulation. PMID 22351773PMID 33407993

Clinical biomarker applications are supported by human studies showing decreased myonectin levels in type 2 diabetes, obesity, and metabolic syndrome. PMID 29161407PMID 31340393PMID 37108038PMID 37782189 Lower levels correlate with poor glycemic control and metabolic parameters, suggesting myonectin could serve both as a predictive marker and potential therapeutic target for metabolic diseases. PMID 37782189PMID 40741175PMID 29161407PMID 31340393