Elucidating exercise-induced skeletal muscle signaling pathways and applying relevant findings to preemptive therapy for lifestyle-related diseases
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- Iwabu Masato
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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- Okada-Iwabu Miki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Laboratory for Advanced Research on Pathophysiology of Metabolic Diseases, The University of Tokyo, Tokyo, Japan
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- Kadowaki Takashi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Toranomon Hospital, Tokyo, Japan
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- Yamauchi Toshimasa
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Abstract
<p>While it is well recognized that exercise represents a radical preventive and therapeutic measure for lifestyle-related diseases, it is clear that contemporary lifestyles abound with situations where exercise may be found difficult to implement on a continuous basis. Indeed, this has led to global expectations for elucidation of the exercise-activated skeletal muscle signaling pathways as well as for development of exercise mimics that effectively activate such pathways. It is shown that exercise activates the transcriptional coactivator PGC-1α via AMPK/SIRT1 in muscle, thereby not only enhancing mitochondrial function and muscle endurance but upregulating energy metabolism. Further, adipocyte-derived adiponectin is also shown to activate AMPK/SIRT1/PGC-1α via its receptor AdipoR1 in skeletal muscles. Thus, adiponectin/AdipoR1 signaling is thought to constitute exercise-mimicking signaling. Indeed, it has become clear that AMPK, SIRT1 and AdipoR activators act as exercise mimetics. With the crystal structures of AdipoR elucidated and humanized AdipoR mice generated toward optimization of candidate AdipoR-activators for human use, expectations are mounting for the clinical application in the near future of AdipoR activators as exercise mimetics in humans. This review provides an overview of molecules activated by exercise and compounds activating these molecules, with a focus on the therapeutic potential of AdipoR activators as exercise mimetics.</p>
Journal
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- Endocrine Journal
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Endocrine Journal 69 (1), 1-8, 2022
The Japan Endocrine Society