Myostatin deficiency is associated with lipidomic abnormalities in skeletal muscles

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. (Résumé d'auteur

Genomic Analysis To Identify Signatures of Artificial Selection and Loci Associated with Important Economic Traits in Duroc Pigs

“…In addition to those significant Go and Pathway terms, a set of artificial selection signatures with extreme P -value coincide with a cluster of genes involved in meat quality, growth, fertility and so on ( Table 2 ). An interesting selection signature was located on SSC15 (104.325-104.8 Mb) and close to the MSTN gene, which was associated with lean muscle mass and played an important role in the process of muscle development ( Baati et al 2017 ). As a commercial pig breed of economic importance, leanness has consistently been considered as an objective trait of Durocs breeding.…”

Transcriptomic analyses reveal rhythmic and CLOCK-driven pathways in human skeletal muscle

“…In addition, we observed an upregulation of MSTN upon siCLOCK, which could further promote the increase in CD36 and FABP3, leading to impaired glucose uptake ( Figure 3D ). Interestingly, muscle-specific myostatin ( Mstn ) KO mice exhibit a reduction of lipid transporters, including FABP3 and CD36, a diminution of lipid oxidation, higher levels of saturated and unsaturated fatty acids, and a decrease of cardiolipin and triglycerides ( Baati et al, 2017 ). Furthermore, downregulation of Mstn in skeletal muscle from type one diabetic mice leads to an increase of Glut1 mRNA and GLUT4 protein levels, promoting insulin-stimulated glucose uptake ( Coleman et al, 2016 ).…”

A comparison of the mitochondrial proteome and lipidome in the mouse and long-lived Pipistrelle bats

“…These findings suggest a potential link between altered fatty acid transport in the atrium and increased atrial fibrillation onset after cardiac surgery [44]. In muscle, reduced FABP3 is associated with Myostatin gene deletion in mice and causes metabolic changes with decreased mitochondria content, disturbance in mitochondrial respiratory function and increased muscle fatigability [45].…”