Muscle satellite cells are functionally impaired in myasthenia gravis: consequences on muscle regeneration

Abstract

Myasthenia gravis (MG) is a neuromuscular disease caused in most cases by anti-acetyl-choline receptor (AChR) autoantibodies that impair neuromuscular signal transmission and affect skeletal muscle homeostasis. Myogenesis is carried out by muscle stem cells called satellite cells (SCs). However, myogenesis in MG had never been explored. The aim of this study was to characterise the functional properties of myasthenic SCs as well as their abilities in muscle regeneration. SCs were isolated from muscle biopsies of MG patients and age-matched controls. We first showed that the number of Pax7+ SCs was increased in muscle sections from MG and its experimental autoimmune myasthenia gravis (EAMG) mouse model. Myoblasts isolated from MG muscles proliferate and differentiate more actively than myoblasts from control muscles. MyoD and MyoG were expressed at a higher level in MG myoblasts as well as in MG muscle biopsies compared to controls. We found that treatment of control myoblasts with MG sera or monoclonal antiAChR antibodies increased the differentiation and MyoG mRNA expression compared to control sera. To investigate the functional ability of SCs from MG muscle to regenerate, we induced muscle regeneration using acute cardiotoxin injury in the EAMG mouse model. We observed a delay in maturation evidenced by a decrease in fibre size and MyoG mRNA expression as well as an increase in fibre number and embryonic myosin heavy-chain mRNA expression. These findings demonstrate for the first time the altered function of SCs from MG compared to control muscles. These alterations could be due to the anti-AChR antibodies via the modulation of myogenic markers resulting in muscle regeneration impairment. In conclusion, the autoimmune attack in MG appears to have unsuspected pathogenic effects on SCs and muscle regeneration, with potential consequences on myogenic signalling pathways,and subsequently on clinical outcome, especially in the case of muscle stress.

Functional skeletal muscle constructs from transdifferentiated human fibroblasts

“…The increases in myotube width and length in the presence of DAPT suggest that it promotes terminal myogenic differentiation by driving committed cells to enter a more advanced differentiation stage as it does in normal myogenesis. Notably, the morphology of the wide and long myotubes in the DOX + CHIR + DAPT condition resembles that of primary human skeletal myotubes 28 . The DOX + CHIR + DAPT condition illustrated in Fig.…”

MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease

“…We sought to determine whether satellite cell dysfunction and impaired regeneration after injury contributes to AR113Q muscle atrophy. To accomplish this, we injected cardiotoxin (CTX) into the tibialis anterior muscle, leading to severe muscle damage and fiber destruction [6,58]. In WT mice, muscle fibers are replenished to their original size by satellite cells 12-14 days after CTX administration [28,58].…”

MBNL1 reverses the proliferation defect of skeletal muscle satellite cells in myotonic dystrophy type 1 by inhibiting autophagy via the mTOR pathway

“…Ki67 is a nuclear protein that is expressed in G1, S, G2, and early mitosis cells, but not in G0-phase cells 72 ; usually, the ratio of Ki67-positive cells can be used to assess the proliferation ability of SSCs 73 . For staining of cultured SSCs, cells were fixed in 4% PFA for 10 min at room temperature.…”