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Effects of luseogliflozin treatment on hyperglycemia-induced muscle atrophy in rats.

ABSTRACT: Diabetes mellitus is recognized as a risk factor for sarcopenia. Luseogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces inflammation and oxidative stress by improving hyperglycemia, subsequently improving hepatosteatosis or kidney dysfunction. However, the effects of SGLT2 inhibitor on the regulation of skeletal muscle mass or function in hyperglycemia are still unknown. In this study, we investigated the effects of luseogliflozin-mediated attenuation of hyperglycemia on the prevention of muscle atrophy. Twenty-four male Sprague-Dawley rats were randomly divided into four groups: control, control with SGLT2 inhibitor treatment, hyperglycemia, and hyperglycemia with SGLT2 inhibitor treatment. The hyperglycemic rodent model was established using a single injection of streptozotocin, a compound with preferential toxicity toward pancreatic beta cells. Muscle atrophy in streptozotocin-induced hyperglycemic model rats was inhibited by the suppression of hyperglycemia using luseogliflozin, which consequently suppressed hyperglycemia-mediated increase in the levels of advanced glycation end products (AGEs) and activated the protein degradation pathway in muscle cells. Treatment with luseogliflozin can restore the hyperglycemia-induced loss in the muscle mass to some degree partly through the inhibition of AGEs-induced or homeostatic disruption of mitochondria-induced activation of muscle degradation.

SUBMITTER: Xie K

PROVIDER: S-EPMC10209601 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Effects of luseogliflozin treatment on hyperglycemia-induced muscle atrophy in rats.

Xie Keyu K Sugimoto Ken K Tanaka Minoru M Akasaka Hiroshi H Fujimoto Taku T Takahashi Toshimasa T Onishi Yuri Y Minami Tomohiro T Yoshida Shino S Takami Yoichi Y Yamamoto Koichi K Rakugi Hiromi H

Journal of clinical biochemistry and nutrition 20230221 3

Diabetes mellitus is recognized as a risk factor for sarcopenia. Luseogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces inflammation and oxidative stress by improving hyperglycemia, subsequently improving hepatosteatosis or kidney dysfunction. However, the effects of SGLT2 inhibitor on the regulation of skeletal muscle mass or function in hyperglycemia are still unknown. In this study, we investigated the effects of luseogliflozin-mediated attenuation of hyperglyce ...[more]

PMID: 37251965

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Project description:BackgroundSodium-glucose cotransporter 2 inhibitors (SGLT2i) are commonly used in the management of type 2 diabetes mellitus (T2DM) and have been found to worsen the reduction of skeletal muscle mass in individuals with T2DM. This study aims to examine the potential of exercise in mitigating the skeletal muscle atrophy induced by SGLT2i treatment.MethodsA rat model of T2DM (40 male Sprague-Dawley rats; T2DM induced by a combination of high-fat diet and streptozotocin) was used to examine the effects of six-week treatment with Dapagliflozin (DAPA, SGLT2i) in combination with either aerobic exercise (AE) or resistance training (RT) on skeletal muscle. T2DM-eligible rats were randomized into the T2DM control group (CON, n = 6), DAPA treatment group (DAPA, n = 6), DAPA combined with aerobic exercise intervention group (DAPA + AE, n = 6), and DAPA combined with resistance training intervention group (DAPA + RT, n = 6). To assess the morphological changes in skeletal muscle, myosin ATPase and HE staining were performed. mRNA expression levels of Atrogin-1, MuRF1, and Myostatin were determined using quantitative PCR. Furthermore, protein expression levels of AKT, p70S6K, mTOR, FoXO1/3A, NF-κB, and MuRF1 were examined through western blotting.ResultsBoth the administration of DAPA alone and the combined exercise intervention with DAPA resulted in significant reductions in blood glucose levels and body weight in rats. However, DAPA alone administration led to a decrease in skeletal muscle mass, whereas RT significantly increased skeletal muscle mass and muscle fiber cross-sectional area. The DAPA + RT group exhibited notable increases in both total protein levels and phosphorylation levels of AKT and p70S6K in skeletal muscle. Moreover, the DAPA, DAPA + AE, and DAPA + RT groups demonstrated downregulation of protein expression (FoXO1/3A) and mRNA levels (Atrogin-1, MuRF1, and Myostatin) associated with muscle atrophy.ConclusionsOur findings provide support for the notion that dapagliflozin may induce skeletal muscle atrophy through mechanisms unrelated to protein metabolism impairment in skeletal muscle, as it does not hinder protein metabolic pathways while reduces muscle atrophy-related genes. Additionally, our observations reveal that RT proves more effective than AE in enhancing skeletal muscle mass and muscle fiber cross-sectional area in rats with T2DM by stimulating protein anabolism within the skeletal muscle.

Project description:IntroductionIn our previous study investigating effects of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, on 24-h glycemic variability by continuous glucose monitoring (CGM), luseogliflozin elicited parallel downward shifts in fasting and postprandial glucose levels. However, further review of individual patients' data revealed that postprandial hyperglycemia was not reduced in some patients, while preprandial glucose was ameliorated in most patients. Therefore, we divided patients into two groups according to their postprandial glucose responses and conducted a post hoc subanalyses to elucidate which factors contributed to the differential effects of luseogliflozin.MethodsThirty-four Japanese type 2 diabetic patients in our previous randomized, double-blind, placebo-controlled, crossover study with 7-day luseogliflozin administration were divided into postprandial glucose responders (PGR, n = 23, ameliorated peak glucose) and postprandial glucose non-responders (PGNR; n = 11, non-ameliorated peak glucose). Baseline characteristics, variations in CGM-measured 24-h glucose levels, and other pharmacodynamic variabilities were compared.ResultsBaseline characteristics did not differ significantly between groups. Placebo-subtracted peak glucose was significantly lowered in PGR and significantly increased in PGNR (-43.8 and 17.9 mg/dL; both p < 0.05). Luseogliflozin significantly lowered "lowest glucose" (defined as the lowest level measured throughout a 24-h period) similarly in PGR and PGNR (-19.2 and -24.0 mg/dL; both p < 0.05), significantly reduced the mean amplitude of glucose excursions in PGR (-15.50 mg/dL; p < 0.05), and increased the area under the curve for plasma glucagon over 24 h in PGNR (median difference vs. placebo: 240 pg/mL h; p < 0.05). Luseogliflozin increased urinary glucose excretion (UGE) and decreased serum insulin by similar magnitudes in both groups.ConclusionsLuseogliflozin diminished glucose fluctuations in most patients by lowering peak glucose to a greater extent than lowest glucose. Luseogliflozin may also lower lowest glucose in patients whose peak glucose was not ameliorated despite increasing UGE. The glucagon increase in PGNR might explain its hypoglycemic effect on postprandial glucose.FundingTaisho Pharmaceutical Co., Ltd, Tokyo, Japan.Trial registrationJapicCTI-142548.

Project description:Introduction: Chemicals, such as MNU (N-methyl-N-nitrosourea) and NaIO3 (sodium iodate), are widely used to induce retinal degeneration in rodents. Streptozotocin (STZ) is an analog of N-acetyl glucosamine in which an MNU moiety is linked to a hexose and has a special toxic effect on insulin-producing pancreatic β-cells. It is commonly used to induce hyperglycemia to model diabetes. While intracerebroventricular injection of STZ can produce Alzheimer's disease independent of hyperglycemia, most retinal studies using STZ focus on the effects of hyperglycemia on the retina, but whether STZ has any impact on retinal cells independent of hyperglycemia is unknown. We aimed to investigate the role of cytotoxicity of STZ in rat retina. Methods: Intravitreal or subcutaneous injection of STZ was performed on newborn rats. Electroretinogram (ERG) and H&E staining investigated retinal function and morphological changes. Retinal cell types, cell death, proliferation, inflammation, and angiogenesis were studied by immunostaining. RNA sequencing was performed to examine the transcriptome changes of retinal cells after intravitreal injection of STZ. Results: Intravitreal (5 μg or 10 μg) or subcutaneous (30 mg/kg) injection of STZ at the early stage of newborn rats couldn't induce hyperglycemia but caused NSIR (Neonatal STZ-induced retinopathy), including reduced ERG amplitudes, retinal rosettes and apoptosis, cell cycle arrest, microglial activation, and delayed retinal angiogenesis. STZ did not affect the early-born retinal cell types but significantly reduced the late-born ones. Short-term and long-term hyperglycemia had no significant effects on the NSIR phenotypes. RNA sequencing revealed that STZ induces oxidative stress and activates the p53 pathway of retinal cells. Locally or systemically, STZ injection after P8 couldn't induce SINR when all retinal progenitors exit the cell cycle. Conclusion: NSIR in rats is independent of hyperglycemia but due to STZ's direct cytotoxic effects on retinal progenitor cells. NSIR is a typical reaction to STZ-induced retinal oxidative stress and DNA damage. This significant finding suggests that NSIR may be a valuable model for studying retinal progenitor DNA damage-related diseases, potentially leading to new insights and treatments.

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Effects of luseogliflozin treatment on hyperglycemia-induced muscle atrophy in rats.

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Effects of luseogliflozin treatment on hyperglycemia-induced muscle atrophy in rats.

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