Document Type

Article

Publication Date

12-8-2020

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Keywords

Activin Receptors, Type I, Activin Receptors, Type II, Activins, Animals, Mice, Inbred C57BL, Muscle Development, Muscle Fibers, Skeletal, Muscles, Myostatin, Organ Size

JAX Source

Proc Natl Acad Sci U S A 2020 Dec 8; 117(49):30907-30917

Volume

117

Issue

49

First Page

30907

Last Page

30917

ISSN

1091-6490

PMID

33219121

DOI

https://doi.org/10.1016/j.stemcr.2020.08.011

Grant

AR060636, AG052962

Abstract

Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.

Comments

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0

Download

Share

COinS