Transforming Growth Factor-Beta in Skeletal Muscle Wasting.

Gordon L Klein

doi:10.3390/ijms23031167

Abstract

Transforming growth factor-beta (TGF-β) is part of a family of molecules that is present in many body tissues and performs many different functions. Evidence has been obtained from mice and human cancer patients with bony metastases and non-metastatic disease, as well as pediatric burn patients, that inflammation leads to bone resorption and release of TGF-β from the bone matrix with paracrine effects on muscle protein balance, possibly mediated by the generation of reactive oxygen species. Whether immobilization, which confounds the etiology of bone resorption in burn injury, also leads to the release of TGF-β from bone contributing to muscle wasting in other conditions is unclear. The use of anti-resorptive therapy in both metastatic cancer patients and pediatric burn patients has been successful in the prevention of muscle wasting, thereby creating an additional therapeutic niche for this class of drugs. The liberation of TGF-β may be one way in which bone helps to control muscle mass, but further investigation will be necessary to assess whether the rate of bone resorption is the determining factor for the release of TGF-β. Moreover, whether different resorptive conditions, such as immobilization and hyperparathyroidism, also involve TGF-β release in the pathogenesis of muscle wasting needs to be investigated.

Highlights

Introduction and Early WorkThis review will discuss the influence of bone resorption on muscle wasting by liberation of transforming growth factor-beta from the matrix of resorbing bone and apparent paracrine catabolic effects on skeletal muscle.Transforming growth factor (TGF)-β is the name for a superfamily of proteins, including myostatin, that functions in the body to affect growth and to stimulate the inflammatory response along with other functions covered elsewhere
The findings from several studies correlated the quantity of TGF-β in skeletal muscle with the amount of fibrosis detected in muscle tissue in mouse models of Duchenne Muscular Dystrophy (DMD; [2–4])
These studies collectively indicate that muscle damage may result in increased TGF-β deposition in muscle, and that neuromuscular degenerative diseases may have TGF-β signaling involved in their pathogenesis

Summary

Introduction and Early Work

This review will discuss the influence of bone resorption on muscle wasting by liberation of transforming growth factor-beta from the matrix of resorbing bone and apparent paracrine catabolic effects on skeletal muscle. Gonzalez et al [6] showed that muscle from a mouse model of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, expressed increased amounts of TGF-β and Smad, increased fibrosis, and induction of fibroadipogenic precursors These studies collectively indicate that muscle damage may result in increased TGF-β deposition in muscle, and that neuromuscular degenerative diseases may have TGF-β signaling involved in their pathogenesis. Work by Abrigo et al [7] indicated that TGF-β in skeletal muscle contributed to muscle fibrosis in DMD disease, and promoted skeletal muscle atrophy by decreasing muscle fiber diameter and amounts of heavy chain myosin (MHC) in muscle tissue These investigators found increasing amounts of the E3 ubiquitin ligase MuRF-1 expression, indicating TGF-β stimulation of the catabolic ubiquitin ligase pathway. While during the first decade of the 21st century there was no evidence for the clinical importance of TGF-β stimulation of muscle wasting in disease states, what was missing was evidence for the origin of the TGF-β that would be found in muscle inasmuch as the initial studies involved direct administration of TGF-β to muscle [7,8]

The Role of Bone

Unanswered Questions