CILP2 exacerbates diabetes-induced muscle atrophy by over-activating skeletal muscle autophagy and inflammation via the P38 MAPK pathway.

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.