Extracellular matrix contribution to disease progression and dysfunction in myopathy

Abstract

Myopathic processes affect skeletal muscle and heart. In the muscular dystrophies, which are a subset of myopathies, muscle cells are gradually replaced by fibrosis and fat, impairing muscle function as well as regeneration and repair. In addition to skeletal muscle, these genetic disorders often also affect the heart, where fibrofatty infiltration progressively accumulates in the myocardium, impairing heart function. Although considerable effort has focused on gene-corrective and gene-replacement approaches to stabilize myofibers and cardiomyocytes, the continual and ongoing deposition of extracellular matrix itself contributes to tissue and organ dysfunction. Transcriptomic and proteomic profiling, along with high-resolution imaging and biophysical measurements, have been applied to define extracellular matrix components and their role in contributing to cardiac and skeletal muscle weakness. More recently, decellularization methods have been adapted to an on-slide format to preserve the spatial geography of the extracellular matrix, allowing new insight into matrix remodeling and its direct role in suppressing regeneration in muscle. This review highlights recent literature with focus on the extracellular matrix and molecular mechanisms that contribute to muscle and heart fibrotic disorders. We will also compare how the myopathic matrix differs from healthy matrix, emphasizing how the pathological matrix contributes to disease.

Keywords: acellular myoscaffolds; decellularization; fibrosis; heart; muscle.

Figure 1.

Sirius Red (collagen stain) demonstrates areas of fibrosis in gastrocnemius, diaphragm, and heart sections from dystrophin-deficient mdx mice, which serve as a model of Duchenne Muscular Dystrophy. The boxed area highlights a region of relatively intact muscle adjacent to regions of intense fibrosis (arrows). The diaphragm muscle is the most fibrotic muscle in this mouse model.

Figure 2.

Schematic of the extracellular matrix and matrisome components important for muscle injury and repair. In skeletal muscle, acute injury leads to acute remodeling of the ECM, which can often fully resolve depending on the extent of the primary insult. In contrast, muscular dystrophy is characterized by ongoing degeneration concomitant with regeneration, which leads to progressive replacement of the myofibers by ECM. Figure created with BioRender.com. ECM, extra-cellular matrix.

Figure 3.

Diagram of the on-slide decellularization process for studying the ECM and its potential downstream applications. Figure created with BioRender.com. ECM, extracellular matrix.