Abstract
Myostatin (Mstn) deficiency leads to skeletal muscle overgrowth and Mstn inhibition is considered as a promising treatment for muscle-wasting disorders. Mstn gene deletion in mice also causes metabolic changes with decreased mitochondria content, disturbance in mitochondrial respiratory function and increased muscle fatigability. However the impact of MSTN deficiency on these metabolic changes is not fully elucidated. Here, we hypothesized that lack of MSTN will alter skeletal muscle membrane lipid composition in relation with pronounced alterations in muscle function and metabolism. Indeed, phospholipids and in particular cardiolipin mostly present in the inner mitochondrial membrane, play a crucial role in mitochondria function and oxidative phosphorylation process. We observed that Mstn KO muscle had reduced fat membrane transporter levels (FAT/CD36, FABP3, FATP1 and FATP4) associated with decreased lipid oxidative pathway (citrate synthase and β-HAD activities) and impaired lipogenesis (decreased triglyceride and free fatty acid content), indicating a role of mstn in muscle lipid metabolism. We further analyzed phospholipid classes and fatty acid composition by chromatographic methods in muscle and mitochondrial membranes. Mstn KO mice showed increased levels of saturated and polyunsaturated fatty acids at the expense of monounsaturated fatty acids. We also demonstrated, in this phenotype, a reduction in cardiolipin proportion in mitochondrial membrane versus the proportion of others phospholipids, in relation with a decrease in the expression of phosphatidylglycerolphosphate synthase and cardiolipin synthase, enzymes involved in cardiolipin synthesis. These data illustrate the importance of lipids as a link by which MSTN deficiency can impact mitochondrial bioenergetics in skeletal muscle.
Highlights
Myostatin (Mstn), a secreted growth factor and member of the TGF-β superfamily, regulates levels of lean muscle mass and body fat content in mice [1]
Myostatin and muscle lipid metabolism Here, we showed that Mstn gene deletion results in reduced lipolytic machinery in Mstn deficient hypertrophic muscles, in line with previous studies showing that oxidative metabolism is diminished in several models of Mstn deficiency [12,13, 15,16,51]
We observed in aged Mstn KO extensor digitorum longus (EDL) muscle a significant increase in glucose transporter type 4 (GLUT4) protein levels, and a decrease in FAT/CD36 protein levels compared to aged WT mice [16]
Summary
Myostatin (Mstn), a secreted growth factor and member of the TGF-β superfamily, regulates levels of lean muscle mass and body fat content in mice [1]. Inactivation of the Mstn gene in mice, or mutations in the bovine [2,3] ovine [4] and human Mstn [5] genes result in a similar phenotype of increased muscle growth. Targeted inhibition of Mstn gene has been considered as a promising treatment for various muscle-wasting disorders [6,7,8,9]. In this case, strategies have been developed to treat muscle dystrophies, muscle wasting and myopathies by blocking the Myostatin/ActRIIB pathway. A better understanding of the mechanisms underlying the muscle phenotype in Mstn knock-out (KO) model is warranted that may improve treatments
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