한빛사 논문
The Jackson Laboratory for Genomic Medicine, University of Connecticut School of Medicine
Se-Jin Leea,b,1, Adam Lehara, Yewei Liua, Chi Hai Lyc,d, Quynh-Mai Phama, Michael Michauda, Renata Rydzike, Daniel W. Youngstrome, Michael M. Shenf, Vesa Kaartineng, Emily L. Germain-Leeh,i, and Thomas A. Randoc,d,j
aThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032; bDepartment of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030; cPaul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305; dDepartment of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305; eDepartment of Orthopaedic Surgery, University of Connecticut School of Medicine, Farmington, CT 06030; fDepartment of Genetics and Development, Columbia University, New York, NY 10032; gDepartment of Biologic and Materials Sciences and Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109; hDepartment of Pediatrics, University of Connecticut School of Medicine, Farmington, CT 06030; iConnecticut Children’s Center for Rare Bone Disorders, Farmington, CT 06032; and jNeurology Service, VA Palo Alto Health Care System, Palo Alto, CA 94304
1To whom correspondence may be addressed.
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.
myostatin, activin, receptors, skeletal muscle
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