๐ค Authors: Linxi Li, Anju Zuo, Ruoyu Yin, Qiangqiang Liu, Chen Liu, Na Li, Dan Xu, Shaomeng Zhang, Jiarui Li, Shengyun Lei, Shiyan Ruan, Tingting Li, Yuan Guo
CTRP9 as a myokine mitigates sarcopenia via the LAMP-2A/NLRP3 pathway.
Sarcopenia, a degenerative condition marked by progressive skeletal muscle atrophy and impaired regeneration, is closely associated with aging, chronic inflammation, and disrupted proteostasis. While macroautophagy has been extensively studied in this context, little of the role of chaperone-mediated autophagy (CMA) has been known.
In this study, we identified C1q/TNF-related protein 9 (CTRP9) as a novel autocrine myokine secreted by skeletal muscle that exerts dual protective functions-pro-differentiative and anti-atrophic. By using a replicative senescence model in C2C12 myoblasts, we observed that CTRP9 expression declined with cellular aging, accompanied by reduced levels of lysosome-associated membrane protein type 2A (LAMP2A), increased nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) accumulation, and elevated interleukin-1ฮฒ (IL-1ฮฒ) secretion.
Similar molecular signatures were detected in skeletal muscle tissues of CTRP9 knockout (KO) mice, further validating its role in vivo. Treatment with the biologically active globular domain of CTRP9 (gCTRP9) restored LAMP2A expression, enhanced CMA activity, and promoted selective degradation of NLRP3, thereby alleviating inflammatory stress and cellular senescence.
Functionally, gCTRP9 restored myogenic differentiation markers (e.g., MYOD1) while suppressing atrophy-related genes (e.g., Fbxo32) and improving fusion potential and myotube integrity. In primary human myoblasts isolated from elderly individuals, CTRP9 and LAMP2A were significantly downregulated, and NLRP3 expression was increased-changes that were partially reversed upon gCTRP9 treatment.
These findings collectively demonstrate that the CTRP9-LAMP2A-NLRP3 axis plays a pivotal role in regulating both muscle regeneration and maintenance. By targeting CMA-mediated NLRP3 degradation, CTRP9 offers a promising therapeutic strategy for combating sarcopenia through coordinated modulation of differentiation pathways and muscle atrophy.
