Impaired muscle stem cell function and abnormal myogenesis in acquired myopathies

Abstract

Skeletal muscle possesses a high plasticity and a remarkable regenerative capacity that relies mainly on muscle stem cells (MuSCs). Molecular and cellular components of the MuSC niche, such as immune cells, play key roles to coordinate MuSC function and to orchestrate muscle regeneration. An abnormal infiltration of immune cells and/or imbalance of pro- and anti-inflammatory cytokines could lead to MuSC dysfunctions that could have long lasting effects on muscle function. Different genetic variants were shown to cause muscular dystrophies that intrinsically compromise MuSC function and/or disturb their microenvironment leading to impaired muscle regeneration that contributes to disease progression. Alternatively, many acquired myopathies caused by comorbidities (e.g., cardiopulmonary or kidney diseases), chronic inflammation/infection, or side effects of different drugs can also perturb MuSC function and their microenvironment. The goal of this review is to comprehensively summarize the current knowledge on acquired myopathies and their impact on MuSC function. We further describe potential therapeutic strategies to restore MuSC regenerative capacity.

Keywords: inflammation; muscle stem cell; myogenesis; myopathies; regeneration; therapeutics.

Figure 1. Schematic overview showing the impact of cardiopulmonary and kidney diseases on MuSC function

Chronic obstructive pulmonary disease (COPD) induces a decrease in IGF-1 levels in the muscle and a low-grade inflammation characterized by an increase of proinflammatory cytokines (TNF-α and IL-6). These alterations contribute to the decreased expression of MYOD, MRF-4 and MYOGENIN proteins that regulate MuSC activation, proliferation, and differentiation. In chronic heart failure (CHF), low grade inflammation is associated with higher apoptosis and proteolysis, decreased IGF-1 and increased angiotensin II protein levels in skeletal muscle. Angiotensin II acts through AT1 receptor to induce a decrease of MYOD, MYF5 and MYOGENIN in MuSCs. In chronic kidney disease (CKD), reduction of IGF-1 expression, imbalance of the renin-angiotensin system (RAS) and low-grade inflammation (e.g., TNF-α and IL-6) contribute to the reduced expression of MyoD, Myf5, and Myog genes in MuSC. In these three comorbidities, dysfunction of the MuSCs participates to muscle atrophy and weakness that contribute to the poor prognosis of the diseases.

Figure 2. Schematic overview showing the main effects of inflammatory and infectious myopathies on MuSC function

Idiopathic inflammatory myositis is characterized by an infiltration of immune cells and/or imbalance of pro- and anti-inflammatory cytokines impairing MuSC function. In both dermatomyositis (DM) and polymyositis (PM) diseases there is an increase in MuSC apoptosis mediated through the excessive accumulation of immune cells. In immune-mediated necrotizing myopathy (IMNM), the MuSC fusion is inhibited due to an imbalance in pro- and anti-inflammatory cytokines. In sporadic inclusion-body myositis (sIBM), paracrine signals from lymphocytes contribute to the reduction in MuSC proliferation and MyoD expression, alongside with MuSC senescence. Infectious myositis are divided in three main causative agents: bacteria, parasites, and viruses. Bacterial infection induces the infiltration of immune cells and/or the secretion of toxins that decrease the activation, proliferation, and differentiation capacity of MuSCs. Parasite infection is characterized by an imbalance of macrophages subpopulation that leads to MuSC apoptosis and lower differentiation and fusion capacity. In viral infection, the infiltration of immune cells and the infection of MuSCs by the viruses modulate the gene expression profile of MuSCs leading to their dysfunction.

Figure 3. Schematic overview showing the impact of drug-induced myopathies on MuSC function

Dexamethasone (glucocorticoid) is associated with an increase in atrophic markers (Murf-1, atrogin-1 and myostatin), a decrease in the expression of MYOD, MYF5 and MYOGENIN, and an increase in the expression of the cell cycle inhibitor p21 that inhibits the activation of MuSCs. Prednisone (glucocorticoid) is associated with a reduction in the expression of PAX7 and MYOGENIN in MuSCs. Statins induce an increase in Atrogin-1 expression and a reduction of PGE2 levels in the muscle, which impair MuSC proliferation. Statins also directly target MuSCs to induce a decrease in MYOD expression and stimulate apoptosis through the release of ROS.