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

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.

Local versus systemic control of bone and skeletal muscle mass by components of the transforming growth factor-β signaling pathway

“…The increases in parameters such as BV/TV and bone mineral density seen upon targeting ALK4 and ALK5 were quite remarkable, reaching levels of 12-to 13-fold in the case of BV/TV and 8-to 9-fold in the case of bone mineral density. We previously reported a similar discrepancy in the magnitude of muscle mass increases resulting from targeting these receptors in myofibers (22). In particular, we observed significant increases in muscle mass upon targeting ACVR2 and ACVR2B but substantially greater increases in muscle mass (up to threefold) upon targeting ALK4 and ALK5.…”

“…It is also possible that changes in muscle mass in some of these studies could also indirectly affect bone structure, for example as a result of changes in mechanical forces exerted by the muscles or changes in release of myokines that signal to bone. In a previous study, we showed that by targeting Acvr2 and Acvr2b in myofibers, we were able to increase muscle mass by 40 to 70% without observing any changes in bone structure by micro-CT analysis (22), suggesting that most, if not all, of the changes that we observed in bone structure described here as a result of pathway inhibition likely reflect modulation of signaling by ligands directly to bone. It is certainly possible, however, that indirect effects from reduced muscle mass in Fst-targeted mice may secondarily affect bone by either mechanism.…”

Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration

“…Our data show that simultaneous myofibre specific knockdown of both Acvr1b and Tgfbr1 is required for muscle hypertrophy, while inhibition of Acvr1b does not affect muscle mass or fibre size and inhibition of Tgfbr1 has only marginal effects. Supporting our data, a recent study showed that simultaneous inhibition of Acvr1b and Tgfbr1 was required to enhance muscle mass, while individual receptor inhibition had little effect (Lee, Lehar et al, 2020). These results indicate that Acvr1b and Tgfbr1 have redundant functions in the regulation of muscle mass.…”

Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs

“…To our knowledge, this is the first study to investigate the effect of the downregulation of both Acvr2b and Acvr2a in adult mice. Indeed, a recent study (69) showed how targeting the Acvr2b and Acvr2a in muscle leads to muscle hypertrophy. In this paper, the authors used a myosin light chain promoter/enhancer that leads to the deletion of the Acvr2b and Acvr2a from E13 days, which may have impacted muscle development from an embryonic stage.…”