[Effects and mechanisms of Shenqi Jiangtang Granules in improving sarcopenia in type 2 diabetes mellitus through multiple targets by regulating glucose and lipid metabolism disorder and mitophagy in skeletal muscle].

This study aims to explore the effects and mechanisms of Shenqi Jiangtang Granules(SJG) in improving sarcopenia in type 2 diabetes mellitus(T2DM) by regulating glucose and lipid metabolism disorders and mitophagy in skeletal muscle. Firstly, the modified T2DM with sarcopenia rat models characterized by glucose and lipid metabolism disorders and sarcopenia were established. After modeling successfully, the model rats received either the low-dose of SJG(L-SJG), the high-dose of SJG(H-SJG), rosiglitazone(RSG), or normal saline(as a vehicle) via gavage for 8 weeks, respectively. In the in vivo study, for the model rats, diabetic phenotypic characteristics, glucose and lipid metabolism indicators were examined; sarcopenia indicators including gastrocnemius mass coefficient, forelimb grip strength, gastrocnemius histopathological features, and the protein expression levels and extent of muscle atrophy markers such as Atrogin-1 and MURF-1 in gastrocnemius were also detected. Additionally, mitochondrial morphology and the protein expression levels of mitophagy markers including Tom20, Beclin1, LC3Ⅱ/LC3Ⅰ, P62 in gastrocnemius, insulin resistance(IR) indicators, and the protein expression levels of key signaling molecules in the insulin receptor substrate 1(IRS1)/phosphatidylinositol 3-kinase(PI3K)/serine-threonine kinase(AKT) pathway in gastrocnemius were assessed, respectively. Secondly, in the in vitro study, the C2C12 myotube cells were treated with high glucose(HG) combined with palmitic acid(PA), followed by intervention with H-SJG-containing serum, RSG, or a mitophagy agonist named by CCCP. The protein expression levels and intensity of mitophagy markers, IR indices, and the protein expression levels of key signaling molecules of the IRS1/PI3K/AKT pathway in cells were detected. In addition, in the network pharmacology and non-targeted muscle metabolomics studies, the "Chinese medicine-component-target" network of SJG was constructed using Cytoscape 3.10.1. The OMIM and Gene Cards databases were used to integrate targets related to T2DM and sarcopenia. The DAVID database was applied to perform Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses on the intersection targets of SJG, T2DM, and sarcopenia. Non-targeted metabolomics was adopted to analyze the characteristics of gastrocnemius in rats, screen the potential biomarkers, and enrich the related metabolic pathways. The results of the above-mentioned study indicated that the effect of SJG in ameliorating sarcopenia in T2DM might be associated with regulation of mitophagy, IR, and the PI3K/AKT signaling pathway. More importantly, the in vivo results showed that both SJG and RSG could improve diabetic phenotypic characteristics, glucose and lipid metabolism disorders, sarcopenia, mitochondrial morphology and the protein expression levels of mitophagy markers in gastrocnemius, IR, and the protein expression levels of key signaling molecules in the IRS1/PI3K/AKT pathway in the model rats. The in vitro results showed that both H-SJG and RSG could improve mitophagy, IR, and activation of the IRS1/PI3K/AKT pathway in the C2C12 myotube cells treated with HG combined with PA, and their effects were generally similar to those of a mitophagy agonist. In conclusion, the authors clarified in this study that SJG can ameliorate sarcopenia in T2DM through multiple targets; its mechanisms are closely related to regulating glucose and lipid metabolism disorder, increasing mitophagy in skeletal muscle, inhibiting IR, and activating the IRS1/PI3K/AKT pathway; its effects are equivalent to the euglycemic agent RSG. This study provides pharmacological evidence for exploring "conventional drugs in new use", namely, the scientific connotation of SJG in treating T2DM with sarcopenia in the clinic.