Myostatin propeptide mutation of the hypermuscular Compact mice decreases the formation of myostatin and improves insulin sensitivity

Kocsis, Tamás and Trencsényi, György and Szabó, Kitti and Baán, Júlia Aliz and Müller, Géza and Mendler, Luca and Garai, Ildikó and Deák, Ferenc and Dux, László and Keller-Pintér, Anikó (2017) Myostatin propeptide mutation of the hypermuscular Compact mice decreases the formation of myostatin and improves insulin sensitivity. AMERICAN JOURNAL OF PHYSIOLOGY: ENDOCRINOLOGY AND METABOLISM, 312 (3). E150-E160. ISSN 0193-1849

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Abstract

The TGF-beta family member myostatin (growth/differentiation factor-8, GDF-8) is a negative regulator of skeletal muscle growth. The hypermuscular Compact mice carry the 12-bp Mstn(Cmpt-dl1Abc) deletion in the sequence encoding the propeptide region of the precursor promyostatin and additional modifier genes of the Compact genetic background contribute to determine the full expression of the phenotype. In this study, by using mice strains carrying mutant or wild-type myostatin alleles with Compact genetic background, and non-mutant myostatin with wild-type background we studied separately the effect of the Mstn(Cmpt-dl1Abc) mutation or the Compact genetic background on morphology, metabolism and signaling. We show that both the Compact myostatin mutation and Compact genetic background account for determination of skeletal muscle size. Despite the increased musculature of Compacts, the absolute size of heart and kidney are not influenced by myostatin mutation; however, the Compact genetic background increases them. Both Compact myostatin and genetic background exhibit systemic metabolic effects. The Compact mutation decreases adiposity, improves whole body glucose uptake, insulin sensitivity and 18FDG uptake of skeletal muscle and white adipose tissue, while the Compact genetic background has opposite effect. Importantly, the mutation does not prevent the formation of mature myostatin; however, a decrease in myostatin level was observed leading to altered activation of Smad2, Smad1/5/8 and Akt, and increased level of pAS160, a Rab-GTPase activating protein responsible for GLUT4 translocation. Based on our analysis the Compact genetic background strengthens the effect of myostatin mutation on muscle mass, but can compensate each other when systemic metabolic effects are compared.

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