Treatments for skeletal muscle abnormalities in heart failure: sodium-glucose transporter 2 and ketone bodies

Various skeletal muscle abnormalities are known to occur in heart failure (HF), and are closely associated with exercise intolerance. Particularly, abnormal energy metabolism caused by mitochondrial dysfunction in skeletal muscle is a cause of decreased endurance exercise capacity. However, to date, no specific drug treatment has been established for the skeletal muscle abnormalities and exercise intolerance occurring in HF patients. Sodium-glucose transporter 2 (SGLT2) inhibitors promote glucose excretion by suppressing glucose reabsorption in the renal tubules, which has a hypoglycemic effect independent of insulin secretion. Recently, large clinical trials have demonstrated that treatment with SGLT2 inhibitors suppresses cardiovascular events in patients who have HF with systolic dysfunction. Mechanisms of the therapeutic effects of SGLT2 inhibitors for HF have been suggested to be diuretic, suppression of neurohumoral factor activation, renal protection, and improvement of myocardial metabolism, but has not been clarified to date. SGLT2 inhibitors are known to increase blood ketone bodies. This suggests that they may improve the abnormal skeletal muscle metabolism in HF, i.e., improve fatty acid metabolism, suppress glycolysis, and utilize ketone bodies in mitochondrial energy production. Ultimately, they may improve aerobic metabolism in skeletal muscle, and suppress anaerobic metabolism and improve aerobic exercise capacity at the level of the anaerobic threshold. The potential actions of such SGLT2 inhibitors explain their effectiveness in HF, and may be candidates for new drug treatments aimed at improving exercise intolerance. In this review, we outlined the effects of SGLT2 inhibitors on skeletal muscle metabolism, with a particular focus on ketone metabolism.

Evidence for a neuromuscular circuit involving hypothalamic Interleukin-6 signaling in the control of skeletal muscle metabolism

Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control, including energy expenditure1, food consumption2, glucose homeostasis2, etc. Here we demonstrated that Interleukin-6 (IL6) activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mice skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1-2 axis is closely associated with firing-rate-related genes in the hypothalamus and with fatty acid oxidation- and mitochondrial-related genes in skeletal muscle of genetically diverse BXD mice strains and humans. Using surgical denervation, pharmacological approaches, and transgenic mice, we showed that the hypothalamic IL6/ERK1/2 pathway requires the a2-adrenergic pathway to modify the fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuitry is required to underpin AMPK/ACC signaling activation and fatty acid oxidation post-exercise. Once the selective downregulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle post-exercise. Altogether, these data demonstrated that IL6/ERK axis in VMH controls fatty acid metabolism in mice skeletal muscle.

Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated ‘omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

Skeletal muscle metabolism on whole-body positron emission tomography during pitching

Background Electromyography (EMG) has been used for evaluating skeletal muscle activity during pitching. However, it is difficult to observe the influence of movement on skeletal muscle activity in deep-lying regions of the trunk and extremities using EMG. An alternative method that may be used is the measurement of glucose metabolism of skeletal muscle using positron emission tomography-computed tomography (PET-CT). This technique is a reliable measure of muscle metabolism, demonstrating a high correlation with the intensity of muscle activity. This study aimed to evaluate whole-body skeletal muscle metabolism during pitching using PET-CT. Methods Ten uninjured, skilled, adult pitchers, who were active at college or professional level, threw 40 baseballs at maximal effort before an intravenous injection of 37 MBq of 18F-fluorodeoxyglucose (FDG). Subsequently, additional 40 balls were pitched. PET-CT images were obtained 50 min after FDG injection, and regions of interest were defined within 72 muscles. The standardized uptake value (SUV) of FDG by muscle tissue per unit volume was calculated, and the mean SUV of the pitchers was compared with that of a healthy adult control group who did not exercise before the measurements. Statistical analysis was performed using a t-test, and P < 0.05 was considered statistically significant. Results Whole-body PET images showed a significant increase in glucose metabolism in the muscle groups of the fingers and toes in both the throwing and non-throwing sides. Additionally, asymmetric increases in glucose metabolism were observed in the muscles of the thigh. Conclusions This is the first study to evaluate whole-body muscle metabolism during pitching using PET-CT. Our findings would be useful in determining the training required for pitchers, and can be further applied to other sporting activities that involve throwing.

Untargeted Metabolomic Characteristics of Skeletal Muscle Dysfunction in Rabbits Induced by a High Fat Diet

Background: Type 2 diabetes and metabolic syndrome caused by a high fat diet (HFD) have become public health problems around the world. These diseases are characterized by disrupted mitochondrial oxidation and insulin resistance in skeletal muscle, but the mechanism is not clear. Therefore, this study aims to reveal how a high-fat diet induces skeletal muscle metabolism disorder.Methods：Sixteen weaned rabbits were randomly divided into two groups, one fed with a standard normal diet (SND) and another one fed a HFD for five weeks. Skeletal muscle tissue samples were extracted from each rabbit at the end of the 5-week trial. An untargeted metabolomics profiling was performed using ultraperformance liquid chromatography combined with mass spectrometry (UHPLC-MS/MS).Results: The HFD significantly altered the expression levels of phospholipids, LCACs, histidine, carnosine and tetrahydrocorticosterone in skeletal muscle. Principal component analysis (PCA) and least square discriminant analysis (PLS-DA) indicated that rabbit skeletal muscle metabolism in the HFD group was significantly up-regulated compared with that of the SND group. Among the 43 skeletal muscle metabolites in the HFD group, phospholipids, LCACs, histidine, carnosine and tetrahydrocorticosterone were identified as biomarkers for skeletal muscle metabolic diseases, and may also serve as potential physiological targets for related diseases in the future.Conclusion: The untargeted metabolomics analysis revealed that a HFD altered the rabbit skeletal muscle metabolism of phospholipids, carnitine, amino acids, and steroids. Notably, phospholipids, LCACs, histidine, carnosine and tetrahydrocorticosterone blocked the oxidative ability of mitochondria, and disturbed the oxidative ability of glucose and the fatty acid-glucose cycle in rabbit skeletal muscle.