Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A

Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):30907-30917. doi: 10.1073/pnas.2019263117.

Se-Jin Lee ¹ ², Adam Lehar ³, Yewei Liu ³, Chi Hai Ly ⁴ ⁵, Quynh-Mai Pham ³, Michael Michaud ³, Renata Rydzik ⁶, Daniel W Youngstrom ⁶, Michael M Shen ⁷, Vesa Kaartinen ⁸, Emily L Germain-Lee ⁹ ¹⁰, Thomas A Rando ⁴ ⁵ ¹¹

Affiliations

1 The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032; [email protected].
2 Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030.
3 The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032.
4 Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.
5 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
6 Department of Orthopaedic Surgery, University of Connecticut School of Medicine, Farmington, CT 06030.
7 Department of Genetics and Development, Columbia University, New York, NY 10032.
8 Department of Biologic and Materials Sciences and Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109.
9 Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT 06030.
10 Connecticut Children's Center for Rare Bone Disorders, Farmington, CT 06032.
11 Neurology Service, VA Palo Alto Health Care System, Palo Alto, CA 94304.

PMID: 33219121 DOI: 10.1073/pnas.2019263117

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.

Keywords

activin; myostatin; receptors; skeletal muscle.

Name
Email *

	Sorry, but the email address you supplied was invalid.