Role of TGF-β signaling in inherited and acquired myopathies

Tyesha N Burks, Ronald D Cohn, Tyesha N Burks, Ronald D Cohn

Abstract

The transforming growth factor-beta (TGF-β) superfamily consists of a variety of cytokines expressed in many different cell types including skeletal muscle. Members of this superfamily that are of particular importance in skeletal muscle are TGF-β1, mitogen-activated protein kinases (MAPKs), and myostatin. These signaling molecules play important roles in skeletal muscle homeostasis and in a variety of inherited and acquired neuromuscular disorders. Expression of these molecules is linked to normal processes in skeletal muscle such as growth, differentiation, regeneration, and stress response. However, chronic elevation of TGF-β1, MAPKs, and myostatin is linked to various features of muscle pathology, including impaired regeneration and atrophy. In this review, we focus on the aberrant signaling of TGF-β in various disorders such as Marfan syndrome, muscular dystrophies, sarcopenia, and critical illness myopathy. We also discuss how the inhibition of several members of the TGF-β signaling pathway has been implicated in ameliorating disease phenotypes, opening up novel therapeutic avenues for a large group of neuromuscular disorders.

Figures

Figure 1
Figure 1
Crosstalk between the canonical and non-canonical transforming growth factor-beta1 (TGF-β1) and myostatin pathways. Once the TGF-β1 or myostatin ligands bind to the appropriate type I and type II receptors, cross-phosphorylation of the type I receptor occurs, leading to the phosphorylation of downstream effectors. In the canonical pathway, the type I receptor phosphorylates Smad2/3, which then binds to Smad4 and translocates into the nucleus to act as transcription factors. In the non-canonical pathway, the type I receptor phosphorylates proteins that are involved in the activation of the mitogen-activated protein kinases (MAPKs). Activated MAPKs can then regulate transcription factors and/or the Smad proteins through direct interactions or via downstream proteins.
Figure 2
Figure 2
Regulated and dysregulated muscle regeneration. In regulated muscle regeneration, a transient inflammatory response occurs upon injury, which includes the chemotaxis of growth factors, cytokines, macrophages, and fibroblasts. This is followed by the activation and proliferation of satellite cells. Once activated, myoblasts differentiate into myocytes, and then fuse together to form myofibers, which exhibit central nuclei. This process is primarily orchestrated by the expression of the myogenic regulatory factors. In dysregulated muscle regeneration, there is a persistent inflammatory response and overexpression of proteins such as transforming growth factor-beta1 (TGF-β1) and myostatin, which promote the formation of fibrotic tissue to replace damaged myofibers.

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