Fibrogenesis in LAMA2-Related Muscular Dystrophy Is a Central Tenet of Disease Etiology

Abstract

LAMA2-related congenital muscular dystrophy, also known as MDC1A, is caused by loss-of-function mutations in the alpha2 chain of Laminin-211. Loss of this protein interrupts the connection between the muscle cell and its extracellular environment and results in an aggressive, congenital-onset muscular dystrophy characterized by severe hypotonia, lack of independent ambulation, and early mortality driven by respiratory complications and/or failure to thrive. Of the pathomechanisms of MDC1A, the earliest and most prominent is widespread and rampant fibrosis. Here, we will discuss some of the key drivers of fibrosis including TGF-beta and renin-angiotensin system signaling and consequences of these pathways including myofibroblast transdifferentiation and matrix remodeling. We will also highlight some of the differences in fibrogenesis in congenital muscular dystrophy (CMD) with that seen in Duchenne muscular dystrophy (DMD). Finally, we will connect the key signaling pathways in the pathogenesis of MDC1A to the current status of the therapeutic approaches that have been tested in the preclinical models of MDC1A to treat fibrosis.

Keywords: TGF-beta; congenital muscular dystrophy; fibrosis; integrin; laminin; myofibroblast; renin–angiotensin system.

FIGURE 1

Histological analysis shows an extensive amount of fibrosis in muscles from DyW mice, a model for MDC1A, during early development. Tibialis anterior muscle isolated from 4 weeks old wild-type (WT) and DyW are stained with Hematoxylin and Eosin (top) and Picrosirius Red (bottom). Representative images show established muscle pathology with fiber size variability, infiltrating cells, and increased interstitial space in the DyW tissue compared to the healthy WT sections (top). Picrosirius red staining of the TA muscle reveals extensive deposition of collagen by 4 weeks of age in these mice. For reference, we have included an image of a muscle biopsy from a seven-year-old boy stained with Hematoxylin and Eosin (Kolbel et al., 2019).

FIGURE 2

Proposed model for signaling pathway of fibrosis in MDC1A. TGF-beta, through integrin-alphaV-mediated activation, leads to upregulation of extra-/matricellular proteins that feedback to activate integrin-alphaV and further activation of TGF-beta. Chronic signaling leads to myofibroblast differentiation and fibrosis. Intervention with Losartan, Halofuginone, or Angiotensin-(1–7) inhibits TGF-beta-mediated fibrosis. OPN, osteopontin; FN, fibronectin; PN, periostin.