Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice
Yazmin I. Rovira Gonzalez, … , George K. Essien Umanah, Kathryn R. Wagner
Yazmin I. Rovira Gonzalez, … , George K. Essien Umanah, Kathryn R. Wagner
Published September 17, 2019
Citation Information: JCI Insight. 2019;4(20):e122247. https://doi.org/10.1172/jci.insight.122247.
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Research Article Metabolism Muscle biology

Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice

Abstract

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.

Authors

Yazmin I. Rovira Gonzalez, Adam L. Moyer, Nicolas J. LeTexier, August D. Bratti, Siyuan Feng, Congshan Sun, Ting Liu, Jyothi Mula, Pankhuri Jha, Shama R. Iyer, Richard Lovering, Brian O’Rourke, Hye Lim Noh, Sujin Suk, Jason K. Kim, George K. Essien Umanah, Kathryn R. Wagner

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Figure 2

Mss51-KO mice show greater mitochondrial respiration but unchanged biogenesis.

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Mss51-KO mice show greater mitochondrial respiration but unchanged bioge...
(A) Abundance of gene expression in quadriceps muscle of Mss51-KO and WT animals. Thirty-three genes corresponding to top 10 significantly affected canonical pathways with FPKM ≥ 5 are shown. Analysis was done in quadriceps muscle of 6-month-old mice on standard chow diet (n = 4 per group, all females). (B) Increased oxygen consumption rate in intact muscle fibers from Mss51-KO mice. Myofibers from the flexor digitorum brevis (FDB) muscle of Mss51-WT and Mss51-KO mice were isolated and subjected to bioenergetic analyses. Intact fibers were consecutively injected with pyruvate (baseline), oligomycin (Oligo), carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), or rotenone/antimycin A (Rot+AA), and oxygen consumption rates (OCRs, pmol/min/fiber) were recorded. (C) Metrics of mitochondrial respiration as calculated from the bioenergetic analysis. All males, 6 weeks old, 1 reading per step (3 repeated measures per mouse fiber isolation, n = 5 per group). (D) Mitochondrial gene copy number analysis in tibialis anterior muscle of 3-month-old Mss51-KO and WT mice normalized to nuclear DNA (n = 7 per group, all females). All data are expressed as mean ± SEM. *P < 0.05 by Student’s t test. (E) Electron microscopy of soleus muscle of 3-month-old female WT and Mss51-KO mice. Left panel magnification, ×9,700 (scale bars = 50 nm); middle and right panel magnification, ×50,000 (scale bars = 500 nm).