International immunopharmacology · 2026
CILP2 exacerbates diabetes-induced muscle atrophy by over-activating skeletal muscle autophagy and inflammation via the P38 MAPK pathway.
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Dong Lun, Chen Siqi, Hu Lingling, Shan Yingying, Xia Yitao, Chen Zhili, Liu Jiaxin, Liu Dongfang, Yang Gangyi, Yang Mengliu, Li Ke
Аннотация
BACKGROUND: Muscle atrophy seriously affects the prognosis of people with diabetes, yet effective interventions remain limited. Although CILP2 is upregulated in skeletal muscle and associated with type 2 diabetes, its potential role in diabetes-induced muscle atrophy remains unknown.
METHODS: A diabetic model was constructed by feeding a high-fat diet combined with intraperitoneal injection of streptozotocin. The regulatory role and mechanism of CILP2 in diabetic muscle atrophy were studied in wild-type mice, CILP2-KO mice, and mice with muscle-specific injection of Ad-GFP or Ad-CILP2. The assessment of muscle atrophy indicators was conducted through the utilization of immunofluorescence, western blotting, and electron microscopy.
RESULTS: CILP2 expression was markedly elevated in the gastrocnemius muscles of ob/ob and db/db mice (all P < 0.01). CILP2 knockdown mitigated diabetes-induced muscle mass loss and dysfunction (P < 0.05), while increasing the muscle fiber CSA (P < 0.05). And the expressions of Atrogin1, MuRF1, LC3II/LC3I and P62 in muscle reduced (all P < 0.05), with an improvement of the autophagy inhibition. Nevertheless, CILP2 overexpression in the gastrocnemius of diabetic mice resulted in a further exacerbation of muscle atrophy, accompanied by a more pronounced autophagy activation (all P < 0.05). CILP2 overexpression exacerbated mature myotubes atrophy induced by palmitic acid, accompanied by increased expressions of Atrogin1, MuRF1 and LC3II/LC3I, and decreased expression of P62 and myotube diameter (all P < 0.05). By inhibiting autophagy, chloroquine mitigated the CILP2 overexpression-induced increase in Atrogin1 expression and reduction in myotube diameter (all P < 0.05). Mechanistically, CILP2 overexpression activated the P38 MAPK pathway in diabetic mice and PA-treated myotubes, consequently triggering the release of IL-1β, IL-6, and TNF-α (all P < 0.05). The P38 inhibitor SB202190 suppressed this cascade, thereby mitigating autophagy overactivation and preventing myotube atrophy (all P < 0.05).
CONCLUSIONS: CILP2 upregulation exacerbated the diabetes-induced muscle atrophy by activating autophagy and inflammation through the P38 MAPK pathway, thereby proposing its inhibition as a promising therapeutic strategy.
METHODS: A diabetic model was constructed by feeding a high-fat diet combined with intraperitoneal injection of streptozotocin. The regulatory role and mechanism of CILP2 in diabetic muscle atrophy were studied in wild-type mice, CILP2-KO mice, and mice with muscle-specific injection of Ad-GFP or Ad-CILP2. The assessment of muscle atrophy indicators was conducted through the utilization of immunofluorescence, western blotting, and electron microscopy.
RESULTS: CILP2 expression was markedly elevated in the gastrocnemius muscles of ob/ob and db/db mice (all P < 0.01). CILP2 knockdown mitigated diabetes-induced muscle mass loss and dysfunction (P < 0.05), while increasing the muscle fiber CSA (P < 0.05). And the expressions of Atrogin1, MuRF1, LC3II/LC3I and P62 in muscle reduced (all P < 0.05), with an improvement of the autophagy inhibition. Nevertheless, CILP2 overexpression in the gastrocnemius of diabetic mice resulted in a further exacerbation of muscle atrophy, accompanied by a more pronounced autophagy activation (all P < 0.05). CILP2 overexpression exacerbated mature myotubes atrophy induced by palmitic acid, accompanied by increased expressions of Atrogin1, MuRF1 and LC3II/LC3I, and decreased expression of P62 and myotube diameter (all P < 0.05). By inhibiting autophagy, chloroquine mitigated the CILP2 overexpression-induced increase in Atrogin1 expression and reduction in myotube diameter (all P < 0.05). Mechanistically, CILP2 overexpression activated the P38 MAPK pathway in diabetic mice and PA-treated myotubes, consequently triggering the release of IL-1β, IL-6, and TNF-α (all P < 0.05). The P38 inhibitor SB202190 suppressed this cascade, thereby mitigating autophagy overactivation and preventing myotube atrophy (all P < 0.05).
CONCLUSIONS: CILP2 upregulation exacerbated the diabetes-induced muscle atrophy by activating autophagy and inflammation through the P38 MAPK pathway, thereby proposing its inhibition as a promising therapeutic strategy.