Cellular senescence-mediated exacerbation of Duchenne muscular dystrophy

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.

Senolytics for Cancer Therapy: Is All that Glitters Really Gold?

“…Notably, the senolytic action of ABT-263 appears to depend on inhibition of BCL-X L and/or BCL-W, while BCL-2 inhibition is dispensable [84,86]. Similar to D+Q, ABT-263 was successful in eliminating senescent cell populations in several disease models including aging-associated bone loss [87], radiation-induced lung fibrosis [88], lung emphysema [89], uterine leiomyoma [90], tau-dependent neurodegenerative disease [91], radiation-induced neurodegeneration [92], myocardial infarction (including ischemia-reperfusion injury) [93,94], heart failure [95], pulmonary hypertension [96], insulin resistance [97], osteoarthritis [98,99], synthetic implant-mediated fibrosis [100], and Duchenne muscular dystrophy [101]. ABT-263 is currently a cornerstone in preclinical studies of senolysis and remains a promising drug for use against both liquid and solid tumors [102][103][104].…”

Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics

“…Similarly, the cell surface protein Cdon, which positively regulates myogenesis, is downregulated in progeria model mice, and MuSC-specific knockout of Cdon promotes γH2AX expression in MuSCs after injury, resulting in impaired muscle regeneration ( Bae et al, 2020 ). In addition to aging, obesity and muscular dystrophy are associated with accumulation of senescent MuSCs ( Kudryashova et al, 2012 ; Mu et al, 2015 ; Roux et al, 2015 ; Zhang et al, 2016 ; Dungan et al, 2020 ; Sugihara et al, 2020 ). Although the disease-specific mechanism of senescence induction remains unknown, senescence in MuSCs can result from reduced mitophagy, TGF-β–induced Smad3 activation, and over-activation of Notch ( Figure 1 ) ( Carlson et al, 2008 ; Mu et al, 2015 ; García-Prat et al, 2016 ).…”

“…Interestingly, mouse knockouts of two other senescence-related genes, p53 and p21 (BubR1H/H; p53-/- and BubR1H/H; p21-/-) impairs the muscle regeneration capacity of the BubR1H/H mice ( Baker et al, 2013 ). Another study reported that senescent FAPs are more abundant in obese humans and a rat model of Duchenne muscular dystrophy; however, the causal link between the increased senescent FAPs and muscle pathology remains unclear ( Dungan et al, 2020 ; Sugihara et al, 2020 ).…”

“…Pharmacological elimination of senescent cells by dasatinib/quercetin treatment also decreased muscle strength and function in aged C57BL/6 mice, which develop age-related muscle loss and inflammation in skeletal muscle ( Xu et al, 2018 ). Another senolytic drug, ABT263, also inhibits production of the SASP factors IL-6, TGF-β, and IL-1β in a rat model of Duchenne muscular dystrophy ( Sugihara et al, 2020 ). Treatment with the NAD + precursor nicotinamide riboside (NR) prevents MuSC senescence and decreases production of SASP factors in aged mice as well as in mdx mice, a model of muscular dystrophy ( Zhang et al, 2016 ).…”

“…Therefore, senolytic agents, which eliminate accumulated senescent cells, have attracted a great deal of attention as potential treatments for age-related diseases, which are frequently associated with chronic inflammation ( Bussian et al, 2018 ; Xu et al, 2018 ; Hickson et al, 2019 ; Justice et al, 2019 ). Multiple aspects of cellular senescence are involved in skeletal muscle physiology and disease ( Kudryashova et al, 2012 ; Saito et al, 2020 ; Sugihara et al, 2020 ), raising the question of whether fundamentally different mechanisms underlie the beneficial and detrimental effects of senescence in skeletal muscle. This review focuses on how senescent cells are involved in skeletal muscle physiology and pathology and how senolytics or pro-senescent therapies (including exercise) could be used to treat diseases of skeletal muscle.…”