In contrast to the liver that is a switching station for processing metabolites in support of other organs and tissues and the adipose tissue that serves as a storage depot of energy and metabolic precursor of lipids, muscle is a major fuel consumer. To meet high aerobic catabolic demands for ATP, muscle secretes myokines that call on liver and adipose tissue to supply adequate fuel. Consistent with this concept, several recent studies indicate that FGF21 is induced in skeletal, heart, and gastrocnemius muscle under conditions that cause local and systemic metabolic stress (18–25). These include patients with a mitochondrial respiratory chain deficiency in myocytes and mice defective in muscular autophagy/mitophagy (20, 26, 27). FGF21 may be an insulin and AKT-regulated myokine and its expression is associated with chronic muscular hyperinsulinemia or lipodystrophy (22, 23). Increases in muscle contraction such as in chronic exercise also upregulates muscular FGF21 production (21, 25). Fe-S cluster-deficient muscles in patients showed a dramatic upregulation of FGF21 expression and elevated levels of circulating FGF21 (20). This indicates that muscle stressed by perturbations in mitochondrial energy metabolism responds by increasing the secretion of FGF21 into the circulation.
