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 2

Glucose decreases the ubiquitination of, and increases the protein abundance of, KLF15.

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Glucose decreases the ubiquitination of, and increases the protein abund...
(A and B) Immunoblot analysis of KLF15 protein (A) and quantitative RT-PCR analysis of Klf15 mRNA (B; n = 4) in C2C12 myotubes exposed to the indicated concentrations of glucose for 24 hours. In A, a representative blot and quantitative data (n = 4) are shown in the left and right panels, respectively. (C) Quantitative RT-PCR analysis of muscle atrophy–related gene expression for myotubes treated as in A. n = 6. (D) Immunoblot analysis of KLF15 in myotubes exposed to 5 or 25 mM glucose in the absence or presence of 15 μM MG132 for 6 hours. A representative blot and quantitative data (n = 2) are shown in the left and right panels, respectively. (E) C2C12 myoblasts expressing HA-ubiquitin (Ub) and FLAG-KLF15 were incubated with 5 or 25 mM glucose for 24 hours and then subjected to immunoprecipitation (IP) with antibodies against FLAG. The resulting precipitates were analyzed by immunoblot with antibodies against HA to detect polyubiquitinated [-(Ub)n] KLF15, and the original cell lysates were analyzed by immunoblot with antibodies against FLAG. Representative data from 3 independent experiments are shown. All quantitative data are means ± SEM for the indicated numbers of independent experiments. *P < 0.05; NS, not significant. Two-way ANOVA with Bonferroni’s post hoc test (A and B) or unpaired t test (C).