Adiponectin Increases Skeletal Muscle Mitochondrial Biogenesis by Suppressing Mitogen-Activated Protein Kinase Phosphatase-1

Adiponectin enhances mitochondrial biogenesis and oxidative metabolism hi skeletal muscle. This study aimed to investigate the underlying mechanisms through which adiponectin induces mitochondrial biogenesis in skeletal muscle. Mitochondrial contents, expression, and activation status of p38 mitogen-activated protein kinase (MAPK) and PPAR gamma coactivator in 1 alpha (PGC-1 alpha) were compared between skeletal muscle samples from adiponectin gene knockout, adiponectin-reconstituted, and control mice. Adenovirus-mediated adiponectin and MAPK phosphatase-1 (MKP1) overexpression were used to verify the relationship of MKP1 and PGC-1 alpha in adiponectin-enhanced mitochondrial biogenesis using cultured C2C12 myotubes and PGC-1 alpha knockout mice. An inhibitory effect of adiponectin on MKP1 gene expression was observed in mouse skeletal muscle and cultured C2C12 myotubes. Overexpression of MKP1 attenuated adiponectin-enhanced mitochondrial biogenesis, with significantly decreased PGC-1 alpha expression and p38 MAPK phosphorylation. Although in vivo adiponectin overexpression reduced MKP1 protein levels, the stimulative effects of adiponectin on mitochondrial biogenesis vanished in skeletal muscle of PGC-1 alpha knockout mice. Therefore, our study indicates that adiponectin enhances p38 MAPK/PGC-1 alpha signaling and mitochondrial biogenesis in skeletal muscle by suppressing MKP1 expression. Diabetes 61:1463-1470, 2012