Modifying muscular dystrophy through transforming growth factor-β

Abstract

Muscular dystrophy arises from ongoing muscle degeneration and insufficient regeneration. This imbalance leads to loss of muscle, with replacement by scar or fibrotic tissue, resulting in muscle weakness and, eventually, loss of muscle function. Human muscular dystrophy is characterized by a wide range of disease severity, even when the same genetic mutation is present. This variability implies that other factors, both genetic and environmental, modify the disease outcome. There has been an ongoing effort to define the genetic and molecular bases that influence muscular dystrophy onset and progression. Modifier genes for muscle disease have been identified through both candidate gene approaches and genome-wide surveys. Multiple lines of experimental evidence have now converged on the transforming growth factor-β (TGF-β) pathway as a modifier for muscular dystrophy. TGF-β signaling is upregulated in dystrophic muscle as a result of a destabilized plasma membrane and/or an altered extracellular matrix. Given the important biological role of the TGF-β pathway, and its role beyond muscle homeostasis, we review modifier genes that alter the TGF-β pathway and approaches to modulate TGF-β activity to ameliorate muscle disease.

Keywords: extracellular matrix; genetic modifier; muscular dystrophy; transforming growth factor-β (TGF-β).

Fig. 1. Fibrosis, fatty and inflammatory infiltrate replace myofibers in advanced dystrophic muscle

H&E staining of human skeletal muscle reveals increased fatty and inflammatory infiltrate and replacement of skeletal muscle fibers by fibrotic tissue (arrows) as Duchenne muscular dystrophy (DMD) pathogenesis progresses from a mild to an advanced state.

Fig. 2. LTBP4 isoforms

LTBP4 differs at the 5′ end. Shown are common LTBP4 proteins produced from alternative promoters. The proline rich “hinge” region is shown in red. Arrows indicate common single nucleotide polymorphisms that modify disease outcome in patients with COPD and DMD.

Fig. 3. Fibrillin superfamily of proteins

LTBPs 1 through 4, and fibrillins 1 through 3 together form the Fibrillin superfamily of proteins. LTBPs and the fibrillins share a similar protein structure and play an integral role in the stability of the extracellular matrix.

Fig. 4. TGFβsecretion and bioavailability are tightly regulated

Secretion and activity of TGFβ are tightly regulated. In a basal state, TGFβ is bound to the LTBPs and kept inactive in the extracellular matrix. Upon muscle injury TGFβ is activated and elicits downstream SMAD signaling, to repair the injury and restore muscle function. Dystrophic muscle is characterized by elevated TGFβ activity, which exacerbates the inflammatory response and aggravates the fibrotic response.