TY - JOUR
T1 - Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice
AU - Rovira Gonzalez, Yazmin I.
AU - Moyer, Adam L.
AU - LeTexier, Nicolas J.
AU - Bratti, August D.
AU - Feng, Siyuan
AU - Sun, Congshan
AU - Liu, Ting
AU - Mula, Jyothi
AU - Jha, Pankhuri
AU - Iyer, Shama R.
AU - Lovering, Richard
AU - O’Rourke, Brian
AU - Noh, Hye Lim
AU - Suk, Sujin
AU - Kim, Jason K.
AU - Essien Umanah, George K.
AU - Wagner, Kathryn R.
N1 - Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019/9/17
Y1 - 2019/9/17
N2 - 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, β-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 with WT controls, indicating an accelerated rate of skeletal muscle metabolism. The expression of genes related to oxidative phosphorylation and fatty acid β-oxidation were enhanced in skeletal muscle of Mss51-KO mice compared with 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 β-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.
AB - 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, β-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 with WT controls, indicating an accelerated rate of skeletal muscle metabolism. The expression of genes related to oxidative phosphorylation and fatty acid β-oxidation were enhanced in skeletal muscle of Mss51-KO mice compared with 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 β-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.
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U2 - 10.1172/jci.insight.122247
DO - 10.1172/jci.insight.122247
M3 - Article
C2 - 31527314
AN - SCOPUS:85077396751
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 20
M1 - e122247
ER -