GSE134519
Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice
Myostatin is a negative regulator of muscle growth and metabolism and its inhibition in mice improves insulin sensitivity, increases glucose uptake into skeletal muscle, and decreases total body fat. A recently described mammalian protein called Mss51 is significantly downregulated with myostatin inhibition. In vitro disruption of Mss51 results in increased levels of ATP, ß-oxidation, glycolysis and oxidative phosphorylation. To determine the in vivo biological function of Mss51 in mice, we disrupted the Mss51 gene by CRISPR/Cas9 and found that Mss51 KO mice have normal muscle weights and fiber-type distribution but reduced fat pads. Myofibers isolated from Mss51 KO mice showed an increased oxygen consumption rate compared to WT controls, indicating an accelerated rate of skeletal muscle metabolism. The expression of genes related to oxidative phosphorylation and fatty acid ß-oxidation were enhanced in skeletal muscle of Mss51 KO mice compared to that of WT mice. We found that mice lacking Mss51 and challenged with a high fat diet were resistant to diet-induced weight gain, had increased whole-body glucose turnover and glycolysis rate, and increased systemic insulin sensitivity and fatty acid ß-oxidation. These findings demonstrate that Mss51 modulates skeletal muscle mitochondrial respiration and regulates whole-body glucose and fatty acid metabolism, making it a potential target for obesity and diabetes. Overall design: RNA-seq analysis of quadriceps muscle of wild type (WT) and Mss51 knockout (Mss51 KO) mice. Total RNA isolated from 4 WT and 4 Mss51 KO quadriceps samples of 6mo female mice were analyzed.