Urocortin 2 promotes hypertrophy and enhances skeletal muscle function through cAMP and insulin/IGF-1 signaling pathways.
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2022
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Objective: Although it is well established that urocortin 2 (Ucn2), a peptide member of the corticotrophin releasing factor (CRF) family, and its
specific corticotrophin-releasing factor 2 receptor (CRF2R) are highly expressed in skeletal muscle, the role of this peptide in the regulation of
skeletal muscle mass and protein metabolism remains elusive.
Methods: To elucidate the mechanisms how Ucn2 directly controls protein metabolism in skeletal muscles of normal mice, we carried out
genetic tools, physiological and molecular analyses of muscles in vivo and in vitro.
Results: Here, we demonstrated that Ucn2 overexpression activated cAMP signaling and promoted an expressive muscle hypertrophy associated
with higher rates of protein synthesis and activation of Akt/mTOR and ERK1/2 signaling pathways. Furthermore, Ucn2 induced a decrease in
mRNA levels of atrogin-1 and in autophagic flux inferred by an increase in the protein content of LC3-I, LC3-II and p62. Accordingly, Ucn2 reduced
both the transcriptional activity of FoxO in vivo and the overall protein degradation in vitro through an inhibition of lysosomal proteolytic activity. In
addition, we demonstrated that Ucn2 induced a fast-to-slow fiber type shift and improved fatigue muscle resistance, an effect that was
completely blocked in muscles co-transfected with mitogen-activated protein kinase phosphatase 1 (MKP-1), but not with dominant-negative Akt
mutant (Aktmt).
Conclusions: These data suggest that Ucn2 triggers an anabolic and anti-catabolic response in skeletal muscle of normal mice probably through
the activation of cAMP cascade and participation of Akt and ERK1/2 signaling. These findings open new perspectives in the development of
therapeutic strategies to cope with the loss of muscle mass.
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Hypertrophy, cAMP, Urocortin 2, Fatigue resistance
Citação
SILVA, N. L. E. da et al. Urocortin 2 promotes hypertrophy and enhances skeletal muscle function through cAMP and insulin/IGF-1 signaling pathways. Molecular Metabolism, v. 60, artigo 101492, 2022. Disponível em: <https://www.sciencedirect.com/science/article/pii/S2212877822000618?via%3Dihub>. Acesso em: 11 out. 2022.