Studies from the last decades indicate that increased levels of ammonia contribute to muscle wasting in critically ill patients. The aim of the article is to examine the effects of two different causes of hyperammonemia-increased ATP degradation in muscles during strenuous exercise and impaired ammonia detoxification to urea due to liver cirrhosis. During exercise, glycolysis, citric acid cycle (CAC) activity, and ATP synthesis in muscles increase. In cirrhosis, due to insulin resistance and mitochondrial dysfunction, glycolysis, CAC activity, and ATP synthesis in muscles are impaired. Both during exercise and in liver cirrhosis, there is increased ammonia detoxification to glutamine (Glu + NH3 + ATP → Gln + ADP + Pi), increased drain of ketoglutarate (α-KG) from CAC for glutamate synthesis by α-KG-linked aminotransferases, glutamate, aspartate, and α-KG deficiency, increased oxidation of branched-chain amino acids (BCAA; valine, leucine, and isoleucine), and protein-energy wasting in muscles. It is concluded that ammonia can contribute to muscle wasting regardless of the cause of its increased levels and that similar strategies can be designed to increase muscle performance in athletes and reduce muscle loss in patients with hyperammonemia. The pros and cons of glutamate, α-KG, aspartate, BCAA, and branched-chain keto acid supplementation are discussed.

• Keywords
• branched-chain amino acids, glutamic acid, glutamine, hyperammonemia,
• Publication type
• Journal Article MeSH
• Review 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

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

Many physiological changes occur with aging. These changes often, directly or indirectly, result in a deterioration of the quality of life and even in a shortening of life expectancy. Besides increased levels of reactive oxygen species, DNA damage and cell apoptosis, another important factor affecting the aging process involves a systemic chronic low-grade inflammation. This condition has already been shown to be interrelated with several (sub)clinical conditions, such as insulin resistance, atherosclerosis and Alzheimer's disease. Recent evidence, however, shows that chronic low-grade inflammation also contributes to the loss of muscle mass, strength and functionality, referred to as sarcopenia, as it affects both muscle protein breakdown and synthesis through several signaling pathways. Classic interventions to counteract age-related muscle wasting mainly focus on resistance training and/or protein supplementation to overcome the anabolic inflexibility from which elderly suffer. Although the elderly benefit from these classic interventions, the therapeutic potential of anti-inflammatory strategies is of great interest, as these might add up to/support the anabolic effect of resistance exercise and/or protein supplementation. In this review, the molecular interaction between inflammation, anabolic sensitivity and muscle protein metabolism in sarcopenic elderly will be addressed.

• Keywords
• NSAID, inflammation, muscle protein metabolism, muscle wasting, protein supplementation, resistance training, sarcopenia,
• Publication type
• Journal Article MeSH
• Review MeSH

Beta-hydroxy-beta-methylbutyrate (HMB) is a metabolite of the essential amino acid leucine that has been reported to have anabolic effects on protein metabolism. The aims of this article were to summarize the results of studies of the effects of HMB on skeletal muscle and to examine the evidence for the rationale to use HMB as a nutritional supplement to exert beneficial effects on muscle mass and function in various conditions of health and disease. The data presented here indicate that the beneficial effects of HMB have been well characterized in strength-power and endurance exercise. HMB attenuates exercise-induced muscle damage and enhances muscle hypertrophy and strength, aerobic performance, resistance to fatigue, and regenerative capacity. HMB is particularly effective in untrained individuals who are exposed to strenuous exercise and in trained individuals who are exposed to periods of high physical stress. The low effectiveness of HMB in strength-trained athletes could be due to the suppression of the proteolysis that is induced by the adaptation to training, which may blunt the effects of HMB. Studies performed with older people have demonstrated that HMB can attenuate the development of sarcopenia in elderly subjects and that the optimal effects of HMB on muscle growth and strength occur when it is combined with exercise. Studies performed under in vitro conditions and in various animal models suggest that HMB may be effective in treatment of muscle wasting in various forms of cachexia. However, there are few clinical reports of the effects of HMB on muscle wasting in cachexia; in addition, most of these studies evaluated the therapeutic potential of combinations of various agents. Therefore, it has not been possible to determine whether HMB was effective or if there was a synergistic effect. Although most of the endogenous HMB is produced in the liver, there are no reports regarding the levels and the effects of HMB supplementation in subjects with liver disease. Several studies have suggested that anabolic effects of HMB supplementation on skeletal muscle do not occur in healthy, non-exercising subjects. It is concluded that (i) HMB may be applied to enhance increases in the mass and strength of skeletal muscles in subjects who exercise and in the elderly and (ii) studies examining the effects of HMB administered alone are needed to obtain conclusions regarding the specific effectiveness in attenuating muscle wasting in various muscle-wasting disorders.

• Keywords
• Cachexia, Exercise, HMB, Leucine, Sarcopenia, Supplements,
• MeSH
• Cachexia diet therapy   physiopathology   MeSH
• Muscle, Skeletal drug effects   physiology   MeSH
• Humans MeSH
• Dietary Supplements MeSH
• Sarcopenia diet therapy   physiopathology   MeSH
• Muscular Atrophy diet therapy   physiopathology   MeSH
• Muscle Strength drug effects   MeSH
• Wasting Syndrome diet therapy   physiopathology   MeSH
• Valerates administration & dosage   pharmacology   MeSH
• Health MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• beta-hydroxyisovaleric acid MeSH Browser
• Valerates MeSH

BACKGROUND: Many people believe in favourable effects of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), especially leucine, on muscle protein balance and consume BCAAs for many years. We determined the effects of the chronic intake of a BCAA- or leucine-enriched diet on protein and amino acid metabolism in fed and postabsorptive states. METHODS: Rats were fed a standard diet, a diet with a high content of valine, leucine, and isoleucine (HVLID), or a high content of leucine (HLD) for 2 months. Half of the animals in each group were sacrificed in the fed state on the last day, and the other half were sacrificed after overnight fast. Protein synthesis was assessed using the flooding dose method (L-[3,4,5-(3)H]phenylalanine), proteolysis on the basis of chymotrypsin-like activity (CHTLA) of proteasome and cathepsin B and L activities. RESULTS: Chronic intake of HVLID or HLD enhanced plasma levels of urea, alanine and glutamine. HVLID also increased levels of all three BCAA and branched-chain keto acids (BCKA), HLD increased leucine, ketoisocaproate and alanine aminotransferase and decreased valine, ketovaline, isoleucine, ketoisoleucine, and LDL cholesterol. Tissue weight and protein content were lower in extensor digitorum longus muscles in the HLD group and higher in kidneys in the HVLID and HLD groups. Muscle protein synthesis in postprandial state was higher in the HVLID group, and CHTLA was lower in muscles of the HVLID and HLD groups compared to controls. Overnight starvation enhanced alanine aminotransferase activity in muscles, and decreased protein synthesis in gastrocnemius (in HVLID group) and extensor digitorum longus (in HLD group) muscles more than in controls. Effect of HVLID and HLD on CHTLA in muscles in postabsorptive state was insignificant. CONCLUSIONS: The results failed to demonstrate positive effects of the chronic consumption of a BCAA-enriched diet on protein balance in skeletal muscle and indicate rather negative effects from a leucine-enriched diet. The primary effects of both diets are an activated catabolism of BCAAs, which leads to an enhanced production of BCKA, alanine and glutamine and their utilization in visceral tissues and an impaired protein synthesis in postabsorptive state, particularly in fast-twitch (white) muscles.

• Keywords
• Glutamine, Muscle, Nutritional supplements, Protein synthesis, Proteolysis, Starvation,
• Publication type
• Journal Article MeSH

Endotoxin administration is frequently used as a model of systemic inflammatory response which is considered the important pathogenetic factor in muscle wasting development in severe illness, such as sepsis, cancer, injury, AIDS and others. The main purpose of this study was determining the effect of various doses of endotoxin on protein and amino acid metabolism in two types of rat skeletal muscle. Sepsis was induced by intraperitoneal administration of endotoxin in a dose of 1, 3 and 5 mg/kg body weight (bw); control animals received a corresponding volume of the saline solution. After 24 h, extensor digitorum longus (EDL) and soleus (SOL) muscles were isolated and used for determination of total and myofibrillar proteolysis, protein synthesis, activity of cathepsins B and L, chymotrypsin-like activity of proteasome and amino acid release. The endotoxemia induced the body weight loss, the rise of total cholesterol and triglyceride plasma concentration and the protein catabolic state in skeletal muscle, which was caused by a higher increase in protein breakdown (due to activation of the proteasome system) than protein synthesis. The more significant effect of endotoxin was seen in EDL than SOL. The dose of 5 mg of endotoxin/kg bw induced the most significant changes in parameters of the protein and amino acid metabolism measured and could be therefore considered appropriate for studies of protein catabolism in young rat skeletal muscle at 24 h after endotoxin treatment.

• MeSH
• Endotoxins pharmacology   MeSH
• Cathepsin B metabolism   MeSH
• Muscle, Skeletal metabolism   MeSH
• Rats MeSH
• Myofibrils metabolism   MeSH
• Rats, Wistar MeSH
• Proteasome Endopeptidase Complex metabolism   MeSH
• Sepsis metabolism   MeSH
• Muscle Proteins metabolism   MeSH
• Dose-Response Relationship, Drug 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
• Endotoxins MeSH
• Cathepsin B MeSH
• Proteasome Endopeptidase Complex MeSH
• Muscle Proteins MeSH

Muscle wasting is a serious complication of various clinical conditions that significantly worsens the prognosis of the illnesses. Clinically relevant models of muscle wasting are essential for understanding its pathogenesis and for selective preclinical testing of potential therapeutic agents. The data presented here indicate that muscle wasting has been well characterized in rat models of sepsis (endotoxaemia, and caecal ligation and puncture), in rat models of chronic renal failure (partial nephrectomy), in animal models of intensive care unit patients (corticosteroid treatment combined with peripheral denervation or with administration of neuromuscular blocking drugs) and in murine and rat models of cancer (tumour cell transplantation). There is a need to explore genetically engineered mouse models of cancer. The degree of protein degradation in skeletal muscle is not well characterized in animal models of liver cirrhosis, chronic heart failure and chronic obstructive pulmonary disease. The major difficulties with all models are standardization and high variation in disease progression and a lack of reflection of clinical reality in some of the models. The translation of the information obtained by using these models to clinical practice may be problematic.

• MeSH
• Muscle, Skeletal metabolism   pathology   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Neoplasms complications   metabolism   pathology   MeSH
• Proteolysis MeSH
• Sepsis complications   metabolism   pathology   MeSH
• Muscular Atrophy etiology   metabolism   pathology   MeSH
• Wasting Syndrome etiology   metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH