Study on Physiological Function of Acetic Acid in Skeletal Muscle

2017岡山県立大学大学

Age-related changes in energy metabolism and skeletal muscle function of Sprague-Dawley rats

As the aging population grows worldwide,the importance of research on aging and agerelated changes is emerging. Aging, as an inevitable process, could lead to physiological functional declines in metabolic, respiratory, and exercise capacity, and could be associated with many diseases. In this study,we examined age-related changes,including O2 consumption volume (VO2), spontaneous locomotor activity,tissue weight, blood biochemical index, and gene expression in skeletal muscle of Sprague-Dawley (SD) rats,aged 32 to 92 weeks. Our findings suggest that the aging process might contribute to a decline in the VO2,spontaneous locomotor activity, and glucose oxidation of rats aged 90 weeks compared to that of rats aged32 weeks. With advancing age, skeletal muscle mass decreased significantly in rats aged 85 weeks (soleus muscle: 0.47 g/kg, gastrocnemius (Gas) muscle: 5.00 g/kg), and 92 weeks (soleus muscle: 0.50 g/kg, Gas muscle: 5.62 g/kg) compared to that in rats aged 32 weeks (soleus muscle: 0.70 g/kg, Gas muscle: 8.89 g/kg).With aging, the levels of genes Myh7, pargc1α, Cycs, and sdha, and mitochondrial DNA, which are related to skeletal muscle function and muscle oxidative capacity, decreased significantly in the soleus muscle of rats aged 85 and 92 weeks compared to that of rats aged 32 weeks. In addition, lipid accumulation in skeletal muscle and weight of white adipose tissue (WAT) around kidney increased with age in rats. This study may clarify age-related changes in energy metabolism, skeletal muscle characteristics, and lipid accumulation in rats, and provide a potential perspective for anti-aging research

酢酸摂取と運動が脂肪代謝と運動耐久性に及ぼす影響

Previously, we found that acetic acid had effects on lipid metabolism in skeletal muscles and has functions that work against obesity and obesity-linked type 2 diabetes through the activation of AMPactivated protein kinase (AMPK). During exercise, AMPK is activated in skeletal muscle according to exercise intensity and it increases fatty acid oxidation. The purpose of this study was to investigate the interactive effects of chronic intake of acetic acid and exercise training on lipid metabolism and endurance performance. Six-week-old SD rats were randomly assigned to four groups: water-injected (rest-water), acetic acid-injected (rest-ace), exercise-trained after injection of water (water-ex), and exercise-trained after injection of acetic acid (ace-ex) for 4 weeks. Body weight (BW) in rest-ace and ace-ex groups was significantly lower than rest-water group. Exercise-training groups showed an increase of exercise capacity, by the addition of intake of acetic acid, lipid oxidation was promoted during exercise tolerance test. Skeletal muscle of rats treated with acetic acid and exercise training led to higher expressions of cytochrome c (cycs), and tended to stimulate expressions of peroxisome proliferator-activated receptor coactivator 1-α (PGC1-α ) and MHC1 genes than those of rest-water group. Those results indicate that treatments both of exercise training and intake of acetic acid contribute to enhancement of lipid metabolism and improvement of exercise capacity.これまで我々は、酢酸の摂取が骨格筋内のAMP活性化プロテインキナーゼ（AMPK）の活性化を介して脂質代謝と肥満、肥満に関連した2型糖尿病の予防に効果があることを示唆してきた。AMPKは運動によって骨格筋で活性化し、脂肪酸酸化を促進する。この研究は、4週間の継続的な酢酸摂取と運動トレーニングが運動中の脂肪代謝と運動耐久性に及ぼす影響について調べることを目的とした。　6週齢のSD系雄ラットを安静期に水を摂取するrest-water群、酢酸を摂取するrest-ace群、運動前に水を摂取するwater-ex群、運動前に酢酸を摂取するace-ex群に無作為に分け実験を行った。酢酸を継続的に摂取すると水摂取に比較して腹腔内脂肪量の減少と体重増加の抑制がみられた。また継続的な酢酸摂取および運動トレーニングにより、耐久性運動下でのグルコース利用の抑制および脂肪酸酸化の促進が見られた。酢酸摂取および運動トレーニング群の腓腹筋では、MHCIおよびcytochrome c等の遅筋線維マーカー遺伝子が増加していた。継続的な酢酸摂取と運動トレーニングにより、脂肪代謝と運動耐久性の向上が示唆された

Acetic acid stimulates G-protein-coupled receptor GPR43 and induces intracellular calcium influx in L6 myotube cells.

Short chain fatty acids (SCFAs) produced endogenously in the gut by bacterial fermentation of dietary fiber have been studied as nutrients that act as signaling molecules to activate G-protein coupled receptors (GPCRs) such as GPR41 and GPR43. GPR43 functioning involves the suppression of lipid accumulation and maintaining body energy homeostasis, and is activated by acetic acid or propionic acid. Previously, we reported that the orally administered acetic acid improves lipid metabolism in liver and skeletal muscles and suppresses obesity, thus improving glucose tolerance. Acetic acid stimulates AMP-activated protein kinase (AMPK) through its metabolic pathway in skeletal muscle cells. We hypothesized that acetic acid would stimulate GPR43 in skeletal muscle cells and has function in modulating gene expression related to muscle characteristics through its signal pathway. The objective of the current study was to clarify this effect of acetic acid. The GPR43 expression, observed in the differentiated myotube cells, was increased upon acetic acid treatment. Acetic acid induced the intracellular calcium influx in the cells and this induction was significantly inhibited by the GPR43-specific siRNA treatment. The calcineurin molecule is activated by calcium/calmodulin and is associated with proliferation of slow-twitch fibers. Calcineurin was activated by acetic acid treatment and inhibited by the concomitant treatment with GPR43-siRNA. Acetic acid induced nuclear localization of myocyte enhancer factor 2A (MEF2A), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and nuclear factor of activated t cells c1 (NFATc1). However, these localizations were abolished by the treatment with GPR43-siRNA. It was concluded that acetic acid plays a role in the activation of GPR43 and involves the proliferation of slow-twitch fibers in L6 skeletal muscles through the calcium-signaling pathway caused by induction of intracellular calcium influx

Effect of Long-Term Supplementation with Acetic Acid on the Skeletal Muscle of Aging Sprague Dawley Rats

Mitochondrial function in skeletal muscle, which plays an essential role in oxidative capacity and physical activity, declines with aging. Acetic acid activates AMP-activated protein kinase (AMPK), which plays a key role in the regulation of whole-body energy by phosphorylating key metabolic enzymes in both biosynthetic and oxidative pathways and stimulates gene expression associated with slow-twitch fibers and mitochondria in skeletal muscle cells. In this study, we investigate whether long-term supplementation with acetic acid improves age-related changes in the skeletal muscle of aging rats in association with the activation of AMPK. Male Sprague Dawley (SD) rats were administered acetic acid orally from 37 to 56 weeks of age. Long-term supplementation with acetic acid decreased the expression of atrophy-related genes, such as atrogin-1, muscle RING-finger protein-1 (MuRF1), and transforming growth factor beta (TGF-β), activated AMPK, and affected the proliferation of mitochondria and type I fiber-related molecules in muscles. The findings suggest that acetic acid exhibits an anti-aging function in the skeletal muscles of aging rats

Taurine Stimulates AMP-Activated Protein Kinase and Modulates the Skeletal Muscle Functions in Rats via the Induction of Intracellular Calcium Influx

Taurine (2-aminoethanesulfonic acid) is a free amino acid abundantly found in mammalian tissues. Taurine plays a role in the maintenance of skeletal muscle functions and is associated with exercise capacity. However, the mechanism underlying taurine function in skeletal muscles has not yet been elucidated. In this study, to investigate the mechanism of taurine function in the skeletal muscles, the effects of short-term administration of a relatively low dose of taurine on the skeletal muscles of Sprague–Dawley rats and the underlying mechanism of taurine function in cultured L6 myotubes were investigated. The results obtained in this study in rats and L6 cells indicate that taurine modulates the skeletal muscle function by stimulating the expression of genes and proteins associated with mitochondrial and respiratory metabolism through the activation of AMP-activated protein kinase via the calcium signaling pathway

Activation of AMP-Activated Protein Kinase and Stimulation of Energy Metabolism by Acetic Acid in L6 Myotube Cells.

Previously, we found that orally administered acetic acid decreased lipogenesis in the liver and suppressed lipid accumulation in adipose tissue of Otsuka Long-Evans Tokushima Fatty rats, which exhibit hyperglycemic obesity with hyperinsulinemia and insulin resistance. Administered acetic acid led to increased phosphorylation of AMP-activated protein kinase (AMPK) in both liver and skeletal muscle cells, and increased transcripts of myoglobin and glucose transporter 4 (GLUT4) genes in skeletal muscle of the rats. It was suggested that acetic acid improved the lipid metabolism in skeletal muscles. In this study, we examined the activation of AMPK and the stimulation of GLUT4 and myoglobin expression by acetic acid in skeletal muscle cells to clarify the physiological function of acetic acid in skeletal muscle cells. Acetic acid added to culture medium was taken up rapidly by L6 cells, and AMPK was phosphorylated upon treatment with acetic acid. We observed increased gene and protein expression of GLUT4 and myoglobin. Uptake of glucose and fatty acids by L6 cells were increased, while triglyceride accumulation was lower in treated cells compared to untreated cells. Furthermore, treated cells also showed increased gene and protein expression of myocyte enhancer factor 2A (MEF2A), which is a well-known transcription factor involved in the expression of myoglobin and GLUT4 genes. These results indicate that acetic acid enhances glucose uptake and fatty acid metabolism through the activation of AMPK, and increases expression of GLUT4 and myoglobin