Outside in: The matrix as a modifier of muscular dystrophy

Abstract

Muscular dystrophies are genetic conditions leading to muscle degeneration and often, impaired regeneration. Duchenne Muscular Dystrophy is a prototypical form of muscular dystrophy, and like other forms of genetically inherited muscle diseases, pathological progression is variable. Variability in muscular dystrophy can arise from differences in the manner in which the primary mutation impacts the affected protein’s function; however, clinical heterogeneity also derives from secondary mutations in other genes that can enhance or reduce pathogenic features of disease. These genes, called genetic modifiers, regulate the pathophysiological context of dystrophic degeneration and regeneration. Understanding the mechanistic links between genetic modifiers and dystrophic progression sheds light on pathologic remodeling, and provides novel avenues to therapeutically intervene to reduce muscle degeneration. Based on targeted genetic approaches and unbiased genomewide screens, several modifiers have been identified for muscular dystrophy, including extracellular agonists of signaling cascades. This review will focus on identification and possible mechanisms of recently identified modifiers for muscular dystrophy, including osteopontin, latent TGFβ binding protein 4 (LTBP4) and Jagged1. Moreover, we will review the investigational approaches that aim to target modifier pathways and thereby counteract dystrophic muscle wasting.

Genetic modifiers of respiratory function in Duchenne muscular dystrophy

“…Both the SPP1 ‐encoded cytokineosteopontin 37 and T‐cell activation mediated by CD40 38 preferentially influence the earlier inflammatory phase of the dystrophic process, rather than the late, end‐stage fibrotic phase 39 . The latter is more affected by latent transforming growth factor β‐binding protein LTBP4, 40 whose disease‐modifying polymorphisms did not show significant effects on PFTs. For LTBP4 , this result did not change when taking into consideration the full VTTT/IAAM haplotype 15 .…”

Long‐range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy

“…Fine mapping of regulatory variants in linkage disequilibrium with the IAAM coding SNPs suggests that the most protective human LTBP4 haplotype combines reduced mRNA expression with tighter latent TGFβ binding, as has been demonstrated for the IAAM protein isoform 10 . When transgenic human LTBP4 VTTT protein isoform is overexpressed in the mdx model, muscle disease is aggravated 36 and sarcolemmal damage of dystrophic muscle fibers is increased 37 . The combination of reduced expression and the LTBP4 IAAM protein isoform known to have less TGFβ release is consistent with mouse models where reduced latent TGFβ bioavailability lessens disease progression in the injured myofiber.…”

KLF10 Gene Expression Modulates Fibrosis in Dystrophic Skeletal Muscle

“…elevated TGF-b signaling activity, and it is this activity that appears to initiate and sustain the fibrotic response to such tissue damage. 10,11 The KLF10 gene is transcriptionally activated as part of the early response to activation of the TGF-b signaling pathway. 21 Because KLF10 is a transcriptional effector of TGF-b signaling, a KLF10 gene knockout mouse model was investigated for its role in regulating normal muscle tissue structure in wild-type mice and for its role in muscle tissue structure in the mdx mouse model of Duchenne muscular dystrophy.…”

“…Ultimately, fibrosis is a major impediment to skeletal muscle recovery of normal structure and function in the dystrophic state. 6,10,11 Transforming growth factor-b (TGF-b) is central to regulation of the regenerative response to skeletal muscle injury and disease as well as the cellular and molecular mechanisms that lead to fibrosis. TGF-b signaling, through membraneassociated TGF-b type I and type II receptors, stimulates fibroblasts to increase production of collagen and fibronectin.…”