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 tolerance and AMPK signaling in skeletal muscle of high-fat diet-induced obese mice, highlighting the efficacy of SPARC treatment in the management of
metabolic diseases. Thus, our findings suggest that SPARC treatment mimics the effects of exercise on
glucose tolerance by enhancing AMPK-dependent
glucose uptake in skeletal muscle.-Aoi, W., Hirano, N., Lassiter, D. G., Björnholm, M., Chibalin, A. V., Sakuma, K., Tanimura, Y., Mizushima, K., Takagi, T., Naito, Y., Zierath, J. R., Krook, A. Secreted
protein acidic and rich in
cysteine (SPARC) improves
glucose tolerance via
AMP-activated protein kinase activation.