Hyperglycemia Promotes Muscle Atrophy through the WWP1/KLF15 Pathway

Background: Evidence suggests that diabetes is a promoting factor of sarcopenia. Mechanism how the condition accelerates the development of sarcopenia remains ambiguous. Results: In streptozotocin (STZ)-induced diabetic mice, skeletal muscle mass was decreased by ∼15 % within 21 days after the STZ treatment. The protein abundance of transcription factor KLF15 as well as the mRNA abundance of proteins related to muscle atrophy (Foxo3a, Atrogin1 and Murf1) were elevated whereas the mRNA of KLF15 was unaltered in skeletal muscle of STZ-diabetic mice. Decrease in skeletal muscle mass and increase in the mRNA abundance of muscle atrophy-related proteins triggered by STZ-induced diabetes were prevented in muscle-specific KLF15 deficient mice suggesting that KLF15 plays a key role in diabetes-induced muscle atrophy. Treatment of C2C12 cells with high concentration of glucose (25 mmol/l) decreased the ubiquitination of and increased the protein abundance of KLF15. The E3 ubiquitin ligase WWP1 was found to be downregulated in skeletal muscle of STZ- diabetic mice and in C2C12 cells treated with glucose. Overexpression and knockdown of WWP1 in C2C12 cells resulted in the decrease and the increase, respectively, of KLF15 protein without affecting its mRNA expression. The mRNA abundance of WWP1 in skeletal muscle was downregulated and the mass of skeletal muscle was reduced in Akita mice, which develop diabetes due to beta-cell dysfunction. Administration of the SGLT2 inhibitor empagliflozin, which lowers glycemia without affecting insulin levels, to Akita mice upregulated the expression of WWP1 in skeletal muscle and increased the skeletal muscle mass of these mice. Conclusion: Our results suggest that hyperglycemia upregulates the protein abundance of KLF15 via the downregulation of WWP1, which catalyzes the ubiquitination of KLF15. Hyperglycemia-induced upregulation of KLF15 leads to the induction of genes for muscle atrophy-related proteins, which in turn promotes the atrophy of skeletal muscle. Disclosure Y. Hirata: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. K. Nomura: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Y. Senga: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. M. Imamura: None. S. Takeda: None. Y. Okada: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. S.J. Burden: None. T. Hosooka: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. W. Ogawa: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Abbott.