Abstract
Duchenne muscular dystrophy (DMD) is a progressive disease characterised by chronic muscle degeneration and inflammation. Our previously established DMD model rats (DMD rats) have a more severe disease phenotype than the broadly used mouse model. We aimed to investigate the role of senescence in DMD using DMD rats and patients. Senescence was induced in satellite cells and mesenchymal progenitor cells, owing to the increased expression of CDKN2A, p16- and p19-encoding gene. Genetic ablation of p16 in DMD rats dramatically restored body weight and muscle strength. Histological analysis showed a reduction of fibrotic and adipose tissues invading skeletal muscle, with increased muscle regeneration. Senolytic drug ABT263 prevented loss of body weight and muscle strength, and increased muscle regeneration in rats even at 8 months—the late stage of DMD. Moreover, senescence markers were highly expressed in the skeletal muscle of DMD patients. In situ hybridization of CDKN2A confirmed the expression of it in satellite cells and mesenchymal progenitor cells in patients with DMD. Collectively, these data provide new insights into the integral role of senescence in DMD progression.
Highlights
Duchenne muscular dystrophy (DMD) is a progressive disease characterised by chronic muscle degeneration and inflammation
Based on our above observation that senescent cells appeared in the skeletal muscle of DMD rats, we focused on the senolytic drug ABT263, which induces the specific depletion of senescent cells[35]
In DMD, the lack of dystrophin causes the degeneration of skeletal muscle, and sustained leakage of cell cytoplasm into the extracellular milieu triggers innate immune responses, including the binding of damage-associated molecular pattern (DAMP) molecules to Toll like receptors (TLRs) on innate immune cells[37]
Summary
Duchenne muscular dystrophy (DMD) is a progressive disease characterised by chronic muscle degeneration and inflammation. Senescence was induced in satellite cells and mesenchymal progenitor cells, owing to the increased expression of CDKN2A, p16- and p19-encoding gene. In situ hybridization of CDKN2A confirmed the expression of it in satellite cells and mesenchymal progenitor cells in patients with DMD. These data provide new insights into the integral role of senescence in DMD progression. Duchenne muscular dystrophy (DMD) is a X-linked muscular dystrophy caused by DMD mutations This gene encodes dystrophin, the structural protein stabilising the plasma membrane of muscle cells, including myofibres and myocardiocytes[1]. Progressive fatty and fibrous tissue deposition is observed as the disease advances Both adipose and fibrous tissues impair skeletal muscle function[5,6]. Under pathological conditions, MPCs differentiate into adipose and fibrous tissues and inhibit, rather than support, muscle r egeneration[8,9]
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