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JCI Insight. 2019 Feb 21;4(4). pii: 124952. doi: 10.1172/jci.insight.124952. eCollection 2019 Feb 21.

Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axis.

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Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Section of Viral Vector Development, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki, Aichi, Japan.
Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan.
Division of Endocrinology and Metabolism, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki, Aichi, Japan.
Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Naha, Okinawa, Japan.
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.


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.


Diabetes; Metabolism; Muscle; Muscle Biology

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