Exercise enhances skeletal muscle regeneration by promoting senescence in fibro-adipogenic progenitors

Abstract

Idiopathic inflammatory myopathies cause progressive muscle weakness and degeneration. Since high-dose glucocorticoids might not lead to full recovery of muscle function, physical exercise is also an important intervention, but some exercises exacerbate chronic inflammation and muscle fibrosis. It is unknown how physical exercise can have both beneficial and detrimental effects in chronic myopathy. Here we show that senescence of fibro-adipogenic progenitors (FAPs) in response to exercise-induced muscle damage is needed to establish a state of regenerative inflammation that induces muscle regeneration. In chronic inflammatory myopathy model mice, exercise does not promote FAP senescence or resistance against tumor necrosis factor-mediated apoptosis. Pro-senescent intervention combining exercise and pharmacological AMPK activation reverses FAP apoptosis resistance and improves muscle function and regeneration. Our results demonstrate that the absence of FAP senescence after exercise leads to muscle degeneration with FAP accumulation. FAPtargeted pro-senescent interventions with exercise and pharmacological AMPK activation may constitute a therapeutic strategy for chronic inflammatory myopathy.

Is exercise a senolytic medicine? A systematic review

“…Moreover, long‐term forced treadmill running showed contradictory effects on the markers of senescent cells, including p16 INK4a , p21 Cip1 , and SA‐β‐Gal (Bao et al, 2020; Jang et al, 2019; Wong et al, 2019; Yoon et al, 2019; Zhang et al, 2016), although four out of five studies showed senolytic effects of exercise in specific tissues under obesity or aging conditions. Conversely, studies on an acute bout of downhill running and prolonged swimming reported an increased level of p21 Cip1 and SA‐β‐Gal in fibro/adipogenic progenitors (Saito et al, 2020), and liver and brain (Huang et al, 2013; Liu et al, 2019), respectively, while another swimming study indicated a reduced level of SA‐β‐Gal in the muscle (Fan et al, 2017). In summary, 10 out of 13 animal studies showed a senolytic effect of exercise, but this effect was influenced by the form and dosage of exercise, type of senescent tissue or cells, and healthy or aging/disease conditions.…”

“…Overall, 16 out of 21 articles were included in the meta‐analysis. However, two studies were excluded because of a lack of essential data (Wu et al, 2019; Zhang et al, 2016), one studies were excluded because of less than two data with similar outcomes and design (Saito et al, 2020), one study was excluded because the data were taken from cohort reported in another study (Tsygankov et al, 2009), and one study was excluded because of the fact that exercise was not an independent factor (Yang et al, 2018).…”

In vivo analysis of γH2AX+ cells in skeletal muscle from aged and obese humans

“…A higher percentage of DNA‐damaged satellite cells could influence the ability of muscle to adapt and regenerate. However, given that a recent report showed that senescent cells, specifically fibro‐adipogenic progenitor cells, are actually required for muscle regeneration, 74 the relative impact, if any, of satellite cell abundance compared to the percentage that are senescent on muscle mass loss with age remains to be determined. Overall, our results show that γH2AX+ satellite cells are rare in resting muscle in vivo (1 per every 200 myofibers) regardless of age.…”

Senolytic drugs: from discovery to translation

“…Other senescent cells, termed here helper-(H-) senescent cells, do not appear to release inflammatory and pro-apoptotic factors substantially and may be involved in promoting stem and progenitor cell determination into appropriate lineages and functions [43,44] (unpublished observations). Hsenescent cells might account for 30 to 70% of senescent cells.…”