Satellite cell contribution to disease pathology in Duchenne muscular dystrophy

Abstract

Progressive muscle weakness and degeneration characterize Duchenne muscular dystrophy (DMD), a lethal, x-linked neuromuscular disorder that affects 1 in 5,000 boys. Loss of dystrophin protein leads to recurrent muscle degeneration, progressive fibrosis, chronic inflammation, and dysfunction of skeletal muscle resident stem cells, called satellite cells. Unfortunately, there is currently no cure for DMD. In this mini review, we discuss how satellite cells in dystrophic muscle are functionally impaired, and how this contributes to the DMD pathology, and the tremendous potential of restoring endogenous satellite cell function as a viable treatment strategy to treat this debilitating and fatal disease.

Keywords: Duchenne muscular dystrophy; asymmetric cell division; dystrophin; muscle regeneration; myogenesis; satellite cells; skeletal muscle stem cells; symmetric cell division.

FIGURE 1

Dystrophin-associated protein complex in healthy and Duchenne muscular dystrophy (DMD) muscle. In healthy muscle (left), dystrophin and its binding partners together form a protein complex called the dystrophin-associated protein complex, which plays numerous signaling and structural roles. This highly organized transmembrane protein complex links the intracellular cytoskeleton with the sarcolemma and the extra-cellular matrix via laminin. In the absence of dystrophin in DMD muscle (right), this protein complex is disassembled, and there is delocalization and loss of expression of several components of the complex. The interaction between F-actin and the extracellular matrix is also lost, resulting in a wide range of deleterious effects that severely compromise the integrity and function of the tissue. Created with BioRender.com.

FIGURE 2

Loss of dystrophin compromises efficient muscle regeneration. In healthy muscle (left), regenerative myogenesis is initiated by activated satellite cells that undergo symmetric cell division to maintain the muscle stem cell pool, as well as asymmetric cell division to give rise to myogenic progenitor cells that expand and contribute to efficient muscle repair and regeneration. In the context of DMD (right), the loss of dystrophin in activated satellite cells results in impaired cell polarity cues, leading to mitotic defects and reduced asymmetric cell divisions. Consequently, the balance favors symmetric stem cell expansion, resulting in satellite cell hyperplasia, and greatly reduced asymmetric cell divisions and myogenic progenitor cell numbers. This impairs muscle regeneration, leading to progressive muscle degeneration and wasting. Created with BioRender.com.

FIGURE 3

The satellite cell phenotype in Duchenne muscular dystrophy (DMD). The cell-intrinsic phenotype of satellite cells in DMD muscle manifests in a variety of ways. The loss of dystrophin impairs satellite cell division, leading to reduced asymmetric cell divisions, myogenic progenitor cells, and compromised regenerative myogenesis. Altered cellular plasticity of satellite cells in response to chronic injury and inflammation contributes to connective tissue deposition. Aberrant mitochondrial morphology, function, and metabolic profile lead to reduced proliferation and functional loss of satellite cells, further exacerbating DMD pathology, particularly in advanced stages of the disease. Elevated expression of senescence markers, mitotic defects, and increased oxidative stress and inflammation are all characteristic of DMD satellite cells and muscle pathology. Further, satellite cells maintain tightly regulated epigenetic control and cell signaling for optimal function. Loss of dystrophin in DMD satellite cells compromises these regulatory mechanisms, affecting satellite cell function at all stages, including maintenance of quiescence, activation, division, proliferation, and differentiation, ultimately contributing to the severe disease pathology in DMD. Created with BioRender.com.