G protein-coupled receptor 81 (GPR81), a selective receptor for lactate, expresses in skeletal muscle cells, but the physiological role of GPR81 in skeletal muscle has not been fully elucidated. As it has been reported that the lactate administration induces muscle hypertrophy, the stimulation of GPR81 has been suggested to mediate muscle hypertrophy. To clarify the contribution of GPR81 activation in skeletal muscle hypertrophy, in the present study, we investigated the effect of GPR81 agonist administration on skeletal muscle mass in mice. Male C57BL/6J mice were randomly divided into control group and GPR81 agonist-administered group that received oral administration of the specific GPR81 agonist 3-Chloro-5-hydroxybenzoic acid (CHBA). In both fast-twitch plantaris and slow-twitch soleus muscles of mice, the protein expression of GPR81 was observed. Oral administration of CHBA to mice significantly increased absolute muscle weight and muscle weight relative to body weight in the two muscles. Moreover, both absolute and relative muscle protein content in the two muscles were significantly increased by CHBA administration. CHBA administration also significantly upregulated the phosphorylation level of p42/44 extracellular signal-regulated kinase-1/2 (ERK1/2) and p90 ribosomal S6 kinase (p90RSK). These observations suggest that activation of GRP81 stimulates increased the mass of two types of skeletal muscle in mice in vivo. Lactate receptor GPR81 may positively affect skeletal muscle mass through activation of ERK pathway.

• MeSH
• Hypertrophy metabolism   MeSH
• Muscle Fibers, Skeletal metabolism   MeSH
• Muscle, Skeletal * metabolism   MeSH
• Lactic Acid * MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Receptors, G-Protein-Coupled MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Lactic Acid * MeSH
• Receptors, G-Protein-Coupled MeSH

The article shows that skeletal muscle plays a dominant role in the catabolism of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) and the pathogenesis of their decreased concentrations in liver cirrhosis, increased concentrations in diabetes, and nonspecific alterations in disorders with signs of systemic inflammatory response syndrome (SIRS), such as burn injury and sepsis. The main role of skeletal muscle in BCAA catabolism is due to its mass and high activity of BCAA aminotransferase, which is absent in the liver. Decreased BCAA levels in liver cirrhosis are due to increased use of the BCAA as a donor of amino group to alpha-ketoglutarate for synthesis of glutamate, which in muscles acts as a substrate for ammonia detoxification to glutamine. Increased BCAA levels in diabetes are due to alterations in glycolysis, citric acid cycle, and fatty acid oxidation. Decreased glycolysis and citric cycle activity impair BCAA transamination to branched-chain keto acids (BCKAs) due to decreased supply of amino group acceptors (alpha-ketoglutarate, pyruvate, and oxaloacetate); increased fatty acid oxidation inhibits flux of BCKA through BCKA dehydrogenase due to increased supply of NADH and acyl-CoAs. Alterations in BCAA levels in disorders with SIRS are inconsistent due to contradictory effects of SIRS on muscles. Specifically, increased proteolysis and insulin resistance tend to increase BCAA levels, whereas activation of BCKA dehydrogenase and glutamine synthesis tend to decrease BCAA levels. The studies are needed to elucidate the role of alterations in BCAA metabolism and the effects of BCAA supplementation on the outcomes of specific diseases.

• MeSH
• Diabetes Mellitus metabolism   MeSH
• Isoleucine metabolism   MeSH
• Liver Cirrhosis metabolism   MeSH
• Muscle, Skeletal metabolism   MeSH
• Leucine metabolism   MeSH
• Humans MeSH
• Metabolic Diseases metabolism   MeSH
• Valine metabolism   MeSH
• Amino Acids, Branched-Chain metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Isoleucine MeSH
• Leucine MeSH
• Valine MeSH
• Amino Acids, Branched-Chain MeSH

This study aimed to examine the effect of eicosapentaenoic acid (EPA) on skeletal muscle hypertrophy induced by muscle overload and the associated intracellular signaling pathways. Male C57BL/6J mice were randomly assigned to oral treatment with either EPA or corn oil for 6 weeks. After 4 weeks of treatment, the gastrocnemius muscle of the right hindlimb was surgically removed to overload the plantaris and soleus muscles for 1 or 2 weeks. We examined the effect of EPA on the signaling pathway associated with protein synthesis using the soleus muscles. According to our analysis of the compensatory muscle growth, EPA administration enhanced hypertrophy of the soleus muscle but not hypertrophy of the plantaris muscle. Nevertheless, EPA administration did not enhance the expression or phosphorylation of Akt, mechanistic target of rapamycin (mTOR), or S6 kinase (S6K) in the soleus muscle. In conclusion, EPA enhances skeletal muscle hypertrophy, which can be independent of changes in the AKT-mTOR-S6K pathway.

• MeSH
• Phosphorylation MeSH
• Hypertrophy chemically induced   metabolism   pathology   MeSH
• Muscle, Skeletal drug effects   metabolism   MeSH
• Eicosapentaenoic Acid therapeutic use   MeSH
• Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Proto-Oncogene Proteins c-akt metabolism   MeSH
• Signal Transduction MeSH
• TOR Serine-Threonine Kinases metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Akt1 protein, mouse MeSH Browser
• Eicosapentaenoic Acid MeSH
• mTOR protein, mouse MeSH Browser
• Proto-Oncogene Proteins c-akt MeSH
• TOR Serine-Threonine Kinases MeSH

Beta-hydroxy-beta-methyl butyrate (HMB) is a unique product of leucine catabolism with positive effects on protein balance. We have examined the effects of HMB (200 mg/kg/day via osmotic pump for 7 days) on rats with diabetes induced by streptozotocin (STZ, 100 mg/kg intraperitoneally). STZ induced severe diabetes associated with muscle wasting, decreased ATP in the liver, and increased α-ketoglutarate in muscles. In plasma, liver, and muscles increased branched-chain amino acids (BCAAs; valine, isoleucine, and leucine) and decreased serine. The decreases in mass and protein content of muscles and increases in BCAA concentration were more pronounced in extensor digitorum longus (fast-twitch muscle) than in soleus muscle (slow-twitch muscle). HMB infusion to STZ-treated animals increased glycemia and serine in the liver, decreased BCAAs in plasma and muscles, and decreased ATP in the liver and muscles. The effects of HMB on the weight and protein content of tissues were nonsignificant. We concluded that fast-twitch muscles are more sensitive to STZ than slow-twitch muscles and that HMB administration to STZ-treated rats has dual effects. Adjustments of BCAA concentrations in plasma and muscles and serine in the liver can be considered beneficial, whereas the increased glycemia and decreased ATP concentrations in the liver and muscles are detrimental.

• Keywords
• ATP depletion, branched-chain amino acids, ketoglutarate, muscles, serine,
• MeSH
• Amino Acids administration & dosage   pharmacology   MeSH
• Diabetes Mellitus, Type 1 chemically induced   drug therapy   metabolism   MeSH
• Injections, Intraperitoneal MeSH
• Injections, Subcutaneous MeSH
• Liver drug effects   metabolism   MeSH
• Muscle, Skeletal drug effects   metabolism   MeSH
• Rats MeSH
• Rats, Wistar MeSH
• Streptozocin administration & dosage   MeSH
• Valerates administration & dosage   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amino Acids MeSH
• beta-hydroxyisovaleric acid MeSH Browser
• Streptozocin MeSH
• Valerates MeSH

The objective of the current study is to present data on the splitting of skeletal muscle fibers in C57BL/6NCrl mice. Skeletal muscles (m. rectus femoris (m. quadriceps femoris)) from 500 (250 female and 250 male) C57BL/6NCrl mice in the 16th week of life were sampled during autopsy and afterwards standardly histologically processed. Results show spontaneous skeletal muscle fiber splitting which is followed by skeletal muscle fiber regeneration. One solitary skeletal muscle fiber is split, or is in contact with few localized splitting skeletal muscle fibers. Part of the split skeletal muscular fiber is phagocytosed, but the remaining skeletal muscular fiber splits are merged into one regenerating skeletal muscle fiber. Nuclei move from the periphery to the regenerating skeletal muscle fiber center during this process. No differences were observed between female and male mice and the morphometry results document < 1 % skeletal muscle fiber splitting. If skeletal muscular fibers splitting occurs 5 % > of all skeletal muscular fibers, it is suggested to describe and calculate this in the final histopathological report.

• MeSH
• Muscle Fibers, Skeletal cytology   physiology   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Histidine (HIS) is investigated for therapy of various disorders and as a nutritional supplement to enhance muscle performance. We examined effects of HIS on amino acid and protein metabolism. Rats consumed HIS in a drinking water at a dose of 0.5 g/l (low HIS), 2 g/l (high HIS) or 0 g/l (control) for 4 weeks. At the end of the study, the animals were euthanized and blood plasma, liver, soleus (SOL), tibialis (TIB), and extensor digitorum longus (EDL) muscles analysed. HIS supplementation increased food intake, body weight and weights and protein contents of the liver and kidneys, but not muscles. In blood plasma there were increases in glucose, urea, and several amino acids, particularly alanine, proline, aspartate, and glutamate and in high HIS group, ammonia was increased. The main findings in the liver were decreased concentrations of methionine, aspartate, and glycine and increased alanine. In muscles of HIS-consuming animals increased alanine and glutamine. In high HIS group (in SOL and TIB) increased chymotrypsin-like activity of proteasome (indicates increased proteolysis); in SOL decreased anserine (beta-alanyl-N1-methylhistidine). We conclude that HIS supplementation increases ammonia production, alanine and glutamine synthesis in muscles, affects turnover of proteins and HIS-containing peptides, and increases requirements for glycine and methionine.

• MeSH
• Amino Acids metabolism   MeSH
• Histidine administration & dosage   MeSH
• Liver metabolism   MeSH
• Random Allocation MeSH
• Rats, Wistar MeSH
• Dietary Supplements MeSH
• Proteasome Endopeptidase Complex metabolism   MeSH
• Muscles metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amino Acids MeSH
• Histidine MeSH
• Proteasome Endopeptidase Complex MeSH

Beta-hydroxy-beta-methylbutyrate (HMB) is a leucine metabolite with protein anabolic effects. We examined the effects of an HMB-enriched diet in healthy rats and rats with liver cirrhosis induced by multiple doses of carbon tetrachloride (CCl4). HMB increased branched-chain amino acids (BCAAs; valine, leucine and isoleucine) in blood and BCAA and ATP in muscles of healthy animals. The effect on muscle mass and protein content was insignificant. In CCl4-treated animals alterations characteristic of liver cirrhosis were found with decreased ratio of the BCAA to aromatic amino acids in blood and lower muscle mass and ATP content when compared with controls. In CCl4-treated animals consuming HMB, we observed higher mortality, lower body weight, higher BCAA levels in blood plasma, higher ATP content in muscles, and lower ATP content and higher cathepsin B and L activities in the liver when compared with CCl4-treated animals without HMB. We conclude that (1) HMB supplementation has a positive effect on muscle mitochondrial function and enhances BCAA concentrations in healthy animals and (2) the effects of HMB on the course of liver cirrhosis in CCl4-treated rats are detrimental. Further studies examining the effects of HMB in other models of hepatic injury are needed to determine pros and cons of HMB in the treatment of subjects with liver cirrhosis.

• Keywords
• branched-chain amino acids, hepatic cachexia, insulin resistance, leucine, liver cirrhosis,
• MeSH
• Carbon Tetrachloride metabolism   MeSH
• Liver Cirrhosis metabolism   MeSH
• Liver drug effects   metabolism   MeSH
• Muscle, Skeletal drug effects   metabolism   MeSH
• Leucine metabolism   MeSH
• Rats, Wistar MeSH
• Dietary Supplements MeSH
• Valerates pharmacology   MeSH
• Amino Acids, Branched-Chain metabolism   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• beta-hydroxyisovaleric acid MeSH Browser
• Carbon Tetrachloride MeSH
• Leucine MeSH
• Valerates MeSH
• Amino Acids, Branched-Chain MeSH

The aim of the study was to examine whether a rat model of liver cirrhosis induced by carbon tetrachloride (CCl4) is a suitable model of muscle wasting and alterations in amino acid metabolism in cirrhotic humans. Rats were treated by intragastric gavage of CCl4 or vehicle for 45 days. Blood plasma and different muscle types-tibialis anterior (mostly white fibres), soleus (red muscle) and extensor digitorum longus (white muscle) - were analysed at the end of the study. Characteristic biomarkers of impaired hepatic function were found in the plasma of cirrhotic animals. The weights and protein contents of all muscles of CCl4-treated animals were lower when compared with controls. Increased concentrations of glutamine (GLN) and aromatic amino acids (phenylalanine and tyrosine) and decreased concentrations of branched-chain amino acids (BCAA), glutamate (GLU), alanine and aspartate were found in plasma and muscles. In the soleus muscle, GLN increased more and GLU and BCAA decreased less than in the extensor digitorum and tibialis muscles. Increased chymotrypsin-like activity (indicating enhanced proteolysis) and decreased α-ketoglutarate and ATP levels were found in muscles of cirrhotic animals. ATP concentration also decreased in blood plasma. It is concluded that a rat model of CCl4-induced cirrhosis is a valid model for the investigation of hepatic cachexia that exhibits alterations in line with a theory of role of ammonia in pathogenesis of BCAA depletion, citric cycle and mitochondria dysfunction, and muscle wasting in cirrhotic subjects. The findings indicate more effective ammonia detoxification to GLN in red than in white muscles.

• Keywords
• ammonia detoxification, cachexia, glutamine, liver cirrhosis,
• MeSH
• Adenosine Triphosphate deficiency   MeSH
• Carbon Tetrachloride pharmacology   MeSH
• Liver Cirrhosis chemically induced   complications   metabolism   pathology   MeSH
• Muscle, Skeletal metabolism   pathology   MeSH
• Ketoglutaric Acids metabolism   MeSH
• Disease Models, Animal MeSH
• Rats, Wistar MeSH
• Eating drug effects   MeSH
• Sarcopenia etiology   metabolism   pathology   MeSH
• Muscle Proteins metabolism   MeSH
• Body Weight drug effects   MeSH
• Organ Size drug effects   MeSH
• Amino Acids, Branched-Chain metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Carbon Tetrachloride MeSH
• Ketoglutaric Acids MeSH
• Muscle Proteins MeSH
• Amino Acids, Branched-Chain MeSH

The aim was to determine the effects of enhanced availability of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) on ammonia detoxification to glutamine (GLN) and protein metabolism in two types of skeletal muscle under hyperammonemic conditions. Isolated soleus (SOL, slow-twitch) and extensor digitorum longus (EDL, fast-twitch) muscles from the left leg of white rats were incubated in a medium with 1 mM ammonia (NH3 group), BCAAs at four times the concentration of the controls (BCAA group) or high levels of both ammonia and BCAA (NH3 + BCAA group). The muscles from the right leg were incubated in basal medium and served as paired controls. L-[1-14C]leucine was used to estimate protein synthesis and leucine oxidation, and 3-methylhistidine release was used to evaluate myofibrillar protein breakdown. We observed decreased protein synthesis and glutamate and α-ketoglutarate (α-KG) levels and increased leucine oxidation, GLN levels, and GLN release into medium in muscles in NH3 group. Increased leucine oxidation, release of branched-chain keto acids and GLN into incubation medium, and protein synthesis in EDL were observed in muscles in the BCAA group. The addition of BCAAs to medium eliminated the adverse effects of ammonia on protein synthesis and adjusted the decrease in α-KG found in the NH3 group. We conclude that (i) high levels of ammonia impair protein synthesis, activate BCAA catabolism, enhance GLN synthesis, and decrease glutamate and α-KG levels and (ii) increased BCAA availability enhances GLN release from muscles and attenuates the adverse effects of ammonia on protein synthesis and decrease in α-KG.

• Keywords
• Ammonia, Branched-chain amino acids, Glutamine, Ketoglutarate, Liver cirrhosis,
• MeSH
• Ammonia poisoning   MeSH
• Citric Acid Cycle drug effects   MeSH
• Glutamine agonists   metabolism   MeSH
• Hyperammonemia enzymology   metabolism   physiopathology   MeSH
• Liver Cirrhosis etiology   metabolism   MeSH
• Ketoglutaric Acids metabolism   MeSH
• Methylhistidines metabolism   MeSH
• Organ Specificity MeSH
• Osmolar Concentration MeSH
• Oxidation-Reduction MeSH
• Rats, Wistar MeSH
• Proteolysis drug effects   MeSH
• Protein Biosynthesis drug effects   MeSH
• Carbon Radioisotopes MeSH
• Muscle Fibers, Slow-Twitch drug effects   enzymology   metabolism   MeSH
• Muscle Fibers, Fast-Twitch drug effects   enzymology   metabolism   MeSH
• Muscle Proteins genetics   metabolism   MeSH
• In Vitro Techniques MeSH
• Amino Acids, Branched-Chain metabolism   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• 3-methylhistidine MeSH Browser
• Ammonia MeSH
• Glutamine MeSH
• Ketoglutaric Acids MeSH
• Methylhistidines MeSH
• Carbon Radioisotopes MeSH
• Muscle Proteins MeSH
• Amino Acids, Branched-Chain MeSH

Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids with protein anabolic properties, which have been studied in a number of muscle wasting disorders for more than 50 years. However, until today, there is no consensus regarding their therapeutic effectiveness. In the article is demonstrated that the crucial roles in BCAA metabolism play: (i) skeletal muscle as the initial site of BCAA catabolism accompanied with the release of alanine and glutamine to the blood; (ii) activity of branched-chain keto acid dehydrogenase (BCKD); and (iii) amination of branched-chain keto acids (BCKAs) to BCAAs. Enhanced consumption of BCAA for ammonia detoxification to glutamine in muscles is the cause of decreased BCAA levels in liver cirrhosis and urea cycle disorders. Increased BCKD activity is responsible for enhanced oxidation of BCAA in chronic renal failure, trauma, burn, sepsis, cancer, phenylbutyrate-treated subjects, and during exercise. Decreased BCKD activity is the main cause of increased BCAA levels and BCKAs in maple syrup urine disease, and plays a role in increased BCAA levels in diabetes type 2 and obesity. Increased BCAA concentrations during brief starvation and type 1 diabetes are explained by amination of BCKAs in visceral tissues and decreased uptake of BCAA by muscles. The studies indicate beneficial effects of BCAAs and BCKAs in therapy of chronic renal failure. New therapeutic strategies should be developed to enhance effectiveness and avoid adverse effects of BCAA on ammonia production in subjects with liver cirrhosis and urea cycle disorders. Further studies are needed to elucidate the effects of BCAA supplementation in burn, trauma, sepsis, cancer and exercise. Whether increased BCAA levels only markers are or also contribute to insulin resistance should be known before the decision is taken regarding their suitability in obese subjects and patients with type 2 diabetes. It is concluded that alterations in BCAA metabolism have been found common in a number of disease states and careful studies are needed to elucidate their therapeutic effectiveness in most indications.

• Keywords
• Ammonia, Cachexia, Cirrhosis, Diabetes, Glutamine, Nutrition,
• Publication type
• Journal Article MeSH
• Review MeSH