Secreted protein acidic and rich in cysteine (SPARC) improves glucose tolerance via AMP-activated protein kinase activation

During exercise, skeletal muscles release cytokines, peptides, and metabolites that exert autocrine, paracrine, or endocrine effects on glucose homeostasis. In this study, we investigated the effects of secreted protein acidic and rich in cysteine (SPARC), an exercise-responsive myokine, on glucose metabolism in human and mouse skeletal muscle. SPARC-knockout mice showed impaired systemic metabolism and reduced phosphorylation of AMPK and protein kinase B in skeletal muscle. Treatment of SPARC-knockout mice with recombinant SPARC improved glucose tolerance and concomitantly activated AMPK in skeletal muscle. These effects were dependent on AMPK-γ3 because SPARC treatment enhanced skeletal muscle glucose uptake in wild-type mice but not in AMPK-γ3–knockout mice. SPARC strongly interacted with the voltage-dependent calcium channel, and inhibition of calcium-dependent signaling prevented SPARC-induced AMPK phosphorylation in human and mouse myotubes. Finally, chronic SPARC treatment improved systemic glucose...