Differential effect of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice.

Yosuke Ikeda,Naoichi Sato,Sachiko Obara,Takashi Miyazawa,Hiroko Otsuka,Masatomo Takahashi,Takeshi Bamba,Hisashi Yokomizo,Yoshihiro Izumi,Shintaro Nakamura,Ryuichi Sakamoto,Yasutaka Miyachi,Motonao Nakao,Yoshihiro Ogawa

doi:10.1042/bcj20210700

Yosuke Ikeda, Naoichi Sato + Show 12 more

Open Access

https://doi.org/10.1042/bcj20210700

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Abstract

There has been a concern that sodium–glucose cotransporter 2 (SGLT2) inhibitors could reduce skeletal muscle mass and function. Here, we examine the effect of canagliflozin (CANA), an SGLT2 inhibitor, on slow and fast muscles from nondiabetic C57BL/6J mice. In this study, mice were fed with or without CANA under ad libitum feeding, and then evaluated for metabolic valuables as well as slow and fast muscle mass and function. We also examined the effect of CANA on gene expressions and metabolites in slow and fast muscles. During SGLT2 inhibition, fast muscle function is increased, as accompanied by increased food intake, whereas slow muscle function is unaffected, although slow and fast muscle mass is maintained. When the amount of food in CANA-treated mice is adjusted to that in vehicle-treated mice, fast muscle mass and function are reduced, but slow muscle was unaffected during SGLT2 inhibition. In metabolome analysis, glycolytic metabolites and ATP are increased in fast muscle, whereas glycolytic metabolites are reduced but ATP is maintained in slow muscle during SGLT2 inhibition. Amino acids and free fatty acids are increased in slow muscle, but unchanged in fast muscle during SGLT2 inhibition. The metabolic effects on slow and fast muscles are exaggerated when food intake is restricted. This study demonstrates the differential effects of an SGLT2 inhibitor on slow and fast muscles independent of impaired glucose metabolism, thereby providing new insights into how they should be used in patients with diabetes, who are at a high risk of sarcopenia.

Highlights

The skeletal muscle is a major metabolic organ regulating glucose homeostasis through insulinstimulated glucose uptake and disposal [1,2]
There was no significant difference in body weight (BW) and random blood glucose (BG) between CANA- and vehicle-treated mice at 2 weeks after the treatment (Figure 1A,B)
Because diabetes is often associated with loss of muscle mass and strength or sarcopenia, it is of great importance to understand how a particular antidiabetic drug could affect skeletal muscle mass and function [28,29]

Summary

Introduction

The skeletal muscle is a major metabolic organ regulating glucose homeostasis through insulinstimulated glucose uptake and disposal [1,2]. It is composed of four major fiber types based on their contractile properties in adult mammals; a slow-twitch fiber expressing myosin heavy chain (MyHC) I and three fast-twitch fibers expressing MyHC IIa, IIx, and IIb [3]. There is considerable evidence that the proportion of slow-twitch oxidative fibers is decreased in disuse-induced skeletal muscle atrophy, obesity, and diabetes [8,9,10,11]. How slow and fast muscles are differently regulated has not been fully understood [13]

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