Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axis
Yu Hirata, Kazuhiro Nomura, Yoko Senga, Yuko Okada, Kenta Kobayashi, Shiki Okamoto, Yasuhiko Minokoshi, Michihiro Imamura, Shin’ichi Takeda, Tetsuya Hosooka, Wataru Ogawa
Yu Hirata, Kazuhiro Nomura, Yoko Senga, Yuko Okada, Kenta Kobayashi, Shiki Okamoto, Yasuhiko Minokoshi, Michihiro Imamura, Shin’ichi Takeda, Tetsuya Hosooka, Wataru Ogawa
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Research Article Metabolism Muscle biology

Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axis

Abstract

Diabetes mellitus is associated with various disorders of the locomotor system including the decline in mass and function of skeletal muscle. The mechanism underlying this association has remained ambiguous, however. We now show that the abundance of the transcription factor KLF15 as well as the expression of genes related to muscle atrophy are increased in skeletal muscle of diabetic model mice, and that mice with muscle-specific KLF15 deficiency are protected from the diabetes-induced decline of skeletal muscle mass. Hyperglycemia was found to upregulate the KLF15 protein in skeletal muscle of diabetic animals, which is achieved via downregulation of the E3 ubiquitin ligase WWP1 and consequent suppression of the ubiquitin-dependent degradation of KLF15. Our results revealed that hyperglycemia, a central disorder in diabetes, promotes muscle atrophy via a WWP1/KLF15 pathway. This pathway may serve as a therapeutic target for decline in skeletal muscle mass accompanied by diabetes mellitus.

Authors

Yu Hirata, Kazuhiro Nomura, Yoko Senga, Yuko Okada, Kenta Kobayashi, Shiki Okamoto, Yasuhiko Minokoshi, Michihiro Imamura, Shin’ichi Takeda, Tetsuya Hosooka, Wataru Ogawa

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Figure 1

Skeletal muscle atrophy associated with diabetes is prevented in mice with skeletal muscle deficiency of KLF15.

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Skeletal muscle atrophy associated with diabetes is prevented in mice wi...
(A–D) Ratio of gastrocnemius or extensor digitorum longus (EDL) muscle mass to body mass (A; n = 12), quantitative reverse transcription PCR (RT-PCR) analysis of Klf15 mRNA in gastrocnemius (B; n = 6), immunoblot analysis of KLF15 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH, loading control) in soleus muscle (nuclear fraction from 3 mice was loaded in 1 lane) (C; n = 2), and quantitative RT-PCR analysis of atrophy-related gene expression in gastrocnemius (D; n = 6) for control mice and diabetes-model mice at 21 days after the onset of STZ administration. (E–H) Ratio of muscle mass to body mass (E; n = 12), histological determination of muscle fiber area in EDL (F and G), and atrophy-related gene expression in gastrocnemius (H; n = 6) for WT or M-KLF15KO mice at 21 days after the onset of STZ administration or vehicle (Cont.) injection. In G, the areas of 500 fibers were measured in each condition. All quantitative data are means ± SEM for the indicated numbers of mice. *P < 0.05, **P < 0.01; NS, not significant. Unpaired t test (A, B, and D) or 2-way ANOVA with Bonferroni’s post hoc test (E, G, and H).