Regulation of fibrosis in muscular dystrophy

Abstract

The production of force and power are inherent properties of skeletal muscle, and regulated by contractile proteins within muscle fibers. However, skeletal muscle integrity and function also require strong connections between muscle fibers and their extracellular matrix (ECM). A well-organized and pliant ECM is integral to muscle function and the ability for many different cell populations to efficiently migrate through ECM is critical during growth and regeneration. For many neuromuscular diseases, genetic mutations cause disruption of these cytoskeletal-ECM connections, resulting in muscle fragility and chronic injury. Ultimately, these changes shift the balance from myogenic pathways toward fibrogenic pathways, culminating in the loss of muscle fibers and their replacement with fatty-fibrotic matrix. Hence a common pathological hallmark of muscular dystrophy is prominent fibrosis. This review will cover the salient features of muscular dystrophy pathogenesis, highlight the signals and cells that are important for myogenic and fibrogenic actions, and discuss how fibrosis alters the ECM of skeletal muscle, and the consequences of fibrosis in developing therapies.

Keywords: Mechanosensing; Muscle regeneration; Satellite cells; Transforming growth factor beta.

Fig. 1

Common fibrotic signaling pathways in skeletal muscle. Diagram of key signaling molecules and mechanisms involved in supporting the fibrotic transcriptional program. Nodes with red text indicate molecules with anti-fibrotic potential under investigation. Nodes shaded in orange depict extracellular molecules, green depict transmembrane molecules, and yellow indicate intracellular molecules. Dashed lines indicate indirect effects. PDGF, Platelet derived growth factor; PDGFR, PDGF receptor; TGFβ, Transforming growth factor beta; LTBP4, latent TGFβ bonding protein 4; TGFβR, TGFβ receptor; MSTN, myostatin; ACVR, activin type 2 receptor; CTGF, connective tissue growth factor; Ang1–7, angiotensin 1–7; Ang1, angiotensin 1; Ang2, angiotensin 2; AT1/2, Angiotensin II receptor type I and II (AT1/2); ACE2, angiotensin converting enzyme 2; ACE1, angiotensin converting enzyme 1. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Diagram of critical cell types in the fibrotic response. Damaged muscle fibers express inflammatory cytokines that activate satellite cells and trigger monocytes into macrophages. Macrophages secrete a number of molecules that regulate muscle repair, fibrosis (Fig. 1) and fibro/adipogenic progenitors (FAP) state. Mis-regulated FAPs develop into myofibroblasts that produce fibrosis. Bold text includes factors secreted/released by cells and large bold font indicates processes of fibrosis and apoptosis. Italic text indicates cell states.

Fig. 3

Properties of the fibrotic matrix in skeletal muscle. Myofibroblasts are the primary ECM secreting cells, which includes the secretion of collagens, proteoglycans, and small mesh forming proteins like lamin, fibronectin, and fibrin. A variety of precursor cells can be transformed into myofibroblasts, but the major sources are FAPs. Matrix degradation is controlled by MMPs, which are inhibited by TIMPs, and activated by Plasminogen activators (PA). PAs support matrix degradation directly and indirectly. Increased strain in the ECM releases TGFβ, stiffens the matrix, and blocks protease susceptibility. Enhanced collagen cross-linking also contributes to the stability of the ECM. Matrix stiffness likely supports the transformation of precursor cells into myofibroblasts to strengthen the fibrotic feedback loop.