Dapagliflozin attenuates skeletal muscle atrophy in diabetic nephropathy mice through suppressing Gasdermin D-mediated pyroptosis.

BACKGROUND: Skeletal muscle atrophy is a clinical concern in diabetic nephropathy, and without effective therapeutic approaches. Massive evidence has demonstrated that dapagliflozin, a sodium-glucose co-transporter 2 inhibitor can relieve diabetic nephropathy by inhibiting glucose re-absorption or podocyte pyroptosis. Nevertheless, whether dapagliflozin could treat skeletal muscle atrophy or the potential protection mechanism in diabetic nephropathy mice is unclear.

METHODS: The variety of approaches were used to assess the particular histology-associated characteristics, mRNA, and protein expression. These included examing the morphology of renal and skeletal muscle tissues through H&E staining, detecting mRNA and protein expression through real-time PCR and Western blot analysis, and monitoring fasting blood glucose levels by using Blood Glucose Monitor Test Kits.

RESULTS: Dapagliflozin mitigated renal tissue injury with podocyte protein-nephrin and skeletal muscle atrophy effectively with mitochondrial-related proteins. Meanwhile, our research revealed that Casp3 was the target gene and dapagliflozin could decrease the expressions. Subsequently, we verified that dapagliflozin can effectively decrease canonical pyroptosis pathway proteins, which include Gasdermin D, NLRP3, Casp1, and ASC. Meanwhile, Palmitic acid (PA) induced Gasdermin E-N fragment (non-canonical pyroptosis protein) in C2C12 cells, and then released the inflammatory molecules such as IL-1β, IL-18, and NF-kappaB, which were suppressed by dapagliflozin treatment. Aside from that, dapagliflozin demonstrated a good binding affinity to the Casp3 and Gasdermin D protein, whereas it had a less binding affinity with NLRP3, Casp1, ASC, and Gasdermin E. At last, the Gasdermin D inhibitor can reverse the therapeutic effect of dapagliflozin.

CONCLUSION: Dapagliflozin alleviates skeletal muscle atrophy in diabetic nephropathy mice, which is through the Gasdermin D-mediated canonical pyroptosis pathway.