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

Tamas Kocsis, Gyorgy Trencsenyi, Kitti Szabo, Julia Aliz Baan, Geza Muller, Luca Mendler, Ildiko Garai, Hans Reinauer, Ferenc Deak, Laszlo Dux, Aniko Keller-Pinter

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4 Citations (Scopus)

Abstract

The TGFβ family member myostatin (growth/differentiation factor-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 the Compact genetic background and nonmutant myostatin with the 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 is 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 and improves whole body glucose uptake, insulin sensitivity, and 18FDG uptake of skeletal muscle and white adipose tissue, whereas the Compact genetic background has the 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 an increased level of p-AS160, a Rab-GTPaseactivating protein responsible for GLUT4 translocation. Based on our analysis, the Compact genetic background strengthens the effect of myostatin mutation on muscle mass, but those can compensate for each other when systemic metabolic effects are compared.

Original languageEnglish
Pages (from-to)E150-E160
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume312
Issue number3
DOIs
Publication statusPublished - Jan 1 2017

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Keywords

  • 2-deoxy-2-[F]fluoro-D-glucose
  • Compact mice
  • Insulin resistance
  • Myostatin
  • Skeletal muscle

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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