Inclisiran ameliorates diabetes-associated skeletal muscle remodeling through modulation of FOXO1/PDK4 and ER stress-UPR signaling

Abstract

Type 2 diabetes mellitus (T2DM) is accompanied by pathological alterations in skeletal muscle, yet effective therapeutic strategies targeting these alterations remain limited. Current interventions, including exercise and nutritional supplementation, often exhibit poor long-term adherence and limited efficacy under diabetic conditions. Therefore, convenient, durable, and metabolically effective therapies are urgently needed. Evidence suggests that excessive endoplasmic reticulum (ER) stress and unfolded protein response (UPR) activation contribute to diabetic skeletal muscle remodeling, while pyruvate dehydrogenase kinase 4 (PDK4) may serve as a key mediator linking metabolic dysfunction to ER stress signaling. A T2DM mouse model was established using high-fat diet feeding combined with streptozotocin administration. Inclisiran was administered intraperitoneally after model establishment. RNA sequencing combined with SVM-RFE analysis identified key targets potentially associated with protective effects of inclisiran. Metabolic parameters, muscle atrophy markers, ER stress/UPR signaling, and muscle fiber type transition were evaluated by real-time qPCR, immunoblotting, and immunofluorescence. Inclisiran significantly reduced fasting blood glucose levels and improved metabolic abnormalities in diabetic mice. Transcriptomic analysis identified PDK4 as a key hub gene potentially associated with pathological alterations in diabetic skeletal muscle and the response to inclisiran treatment. Diabetic mice exhibited marked activation of ER stress/UPR signaling and increased expression of FOXO1, PDK4, and FBX32, whereas inclisiran treatment significantly suppressed these alterations. Additionally, inclisiran partially reversed diabetes-induced muscle fiber type transition from oxidative to glycolytic phenotypes. Inclisiran was associated with improved metabolic abnormalities and favorable alterations in skeletal muscle molecular and fiber-type remodeling in diabetic mice. Transcriptomic analysis identified PDK4 as a potential molecular factor associated with these skeletal muscle alterations. Inclisiran treatment was associated with reduced expression of FOXO1, PDK4, and ER stress-UPR-related markers, together with partial preservation of skeletal muscle fiber-type homeostasis. These findings provide preliminary molecular and histological evidence supporting a potential protective effect of inclisiran on diabetes-associated skeletal muscle remodeling.