Improved endurance capacity of diabetic mice during SGLT2 inhibition: Role of AICARP, an AMPK activator in the soleus

Abstract

BackgroundDiabetes is associated with an increased risk of deleterious changes in muscle mass and function or sarcopenia, leading to physical inactivity and worsening glycaemic control. Given the negative energy balance during sodium–glucose cotransporter‐2 (SGLT2) inhibition, whether SGLT2 inhibitors affect skeletal muscle mass and function is a matter of concern. However, how SGLT2 inhibition affects the skeletal muscle function in patients with diabetes remains insufficiently explored. We aimed to explore the effects of canagliflozin (CANA), an SGLT2 inhibitor, on skeletal muscles in genetically diabetic db/db mice focusing on the differential responses of oxidative and glycolytic muscles.MethodsDb/db mice were treated with CANA for 4 weeks. We measured running distance and handgrip strength to assess skeletal muscle function during CANA treatment. At the end of the experiment, we performed a targeted metabolome analysis of the skeletal muscles.ResultsCANA treatment improved the reduced endurance capacity, as revealed by running distance in db/db mice (414.9 ± 52.8 vs. 88.7 ± 22.7 m, P < 0.05). Targeted metabolome analysis revealed that 5‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranosyl 5′‐monophosphate (AICARP), a naturally occurring AMP‐activated protein kinase (AMPK) activator, increased in the oxidative soleus muscle (P < 0.05), but not in the glycolytic extensor digitorum longus muscle (P = 0.4376), with increased levels of AMPK phosphorylation (P < 0.01).ConclusionsThis study highlights the potential role of the AICARP/AMPK pathway in oxidative rather than glycolytic skeletal muscles during SGLT2 inhibition, providing novel insights into the mechanism by which SGLT2 inhibitors improve endurance capacity in patients with type 2 diabetes.

High-intensity interval training using electrical stimulation ameliorates muscle fatigue in chronic kidney disease-related cachexia by restoring mitochondrial respiratory dysfunction

“…AMPK is also known to be an upstream factor that promotes the organization of the mitochondrial supercomplex ( Han et al, 2022 ). Interestingly, Nakamura et al recently reported that treatment with sodium–glucose cotransporter-2 (SGLT2) inhibitors, which have been shown to significantly attenuate the progression of CKD ( Herrington et al, 2023 ), improved muscle endurance via AMPK activation in a diabetic murine model ( Nakamura et al, 2023 ). This finding suggests that activation of AMPK by HIIT with ES is at least one of the upstream signals that improve muscle endurance, promoting mitochondrial biogenesis and supercomplex formation in muscle with CKD-induced cachexia.…”