Abstract Rationale Chronic obstructive pulmonary disease (COPD) is characterized by accelerated lung aging and accumulation of senescent cells, which secrete a complex mixture of cytokines, chemokines, and growth factors collectively termed the senescence-associated secretory phenotype (SASP). COPD also involves clinically significant skeletal muscle dysfunction, yet the mechanisms linking pulmonary senescence to muscle impairment, particularly the impact on Muscle Stem Cells (MuSCs) critical for muscle repair, remain poorly understood. We hypothesized that lung-derived SASP mediates systemic spread of senescence that drives MuSCs dysfunction and skeletal muscle impairment in COPD, and that targeting senescent cells could mitigate these systemic effects. Methods Circulating SASP factors were profiled in patients with COPD and sarcopenia and integrated with analyses of public human lung transcriptomic datasets and skeletal muscle transcriptomics from cigarette smoke-induced COPD mice. Plasma from COPD mice was applied to MuSCs in vitro to assess proliferation, differentiation, and mitochondrial function. Lung-specific senescence was induced via targeted manipulation of pulmonary epithelial cells to test causal effects on MuSCs. Senolytic treatment with dasatinib plus quercetin (DQ) was administered to evaluate therapeutic potential. Results Patients with COPD and sarcopenia exhibited elevated circulating SASP factors, which inversely correlated with muscle strength. Re-analysis of public human lung transcriptomic datasets and single-cell data confirmed enrichment of SASP-related genes in senescent pulmonary cells. CS-exposed mice showed senescence in both lung and skeletal muscle, and plasma from these mice impaired MuSCs proliferation, differentiation, and mitochondrial function in vitro. Targeted induction of pulmonary senescence in mice reproduced these effects in MuSCs, establishing a causal lung-to-muscle link. DQ treatment reduced systemic SASP levels and restored muscle structure and function. Conclusions Lung-derived senescence-associated secretory factors (SASP) mediate the systemic spread of senescence, impairing muscle stem cell (MuSC) function and skeletal muscle homeostasis in COPD. Pharmacological clearance of senescent cells disrupted this lung-muscle senescence axis, highlighting a potential therapeutic strategy for COPD-related sarcopenia. This abstract is funded by: None
Wang et al. (Fri,) studied this question.