Gene/Protein Disease Symptom Drug Enzyme Compound
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Many types of drugs are used by athletes to improve performance. This paper reviews the literature on 3 categories of drugs: those that enhance performance as stimulants (amphetamines, ephedrine, and cocaine), those that are used to reduce tremor and heart rate (beta-blockers) and those involved in bodyweight gain or loss (anabolic-androgenic steroids, growth hormone, beta 2-agonists, and diuretics). Limitations of research on these drugs as they relate to performance enhancement are also discussed. The numerous studies that have assessed the effects of amphetamines on performance report equivocal results. This may be due to the large interindividual variability in the response to the drug and the small sample sizes used. Most studies, however, show that some individuals do improve exercise performance when taking amphetamines, which may be attributed to their role in masking fatigue. As a stimulant, ephedrine has not been found to improve performance in the few studies available. More recently, ephedrine has been purported to be effective as a fat burner and used by athletes to maintain or improve muscle mass. Although research on individuals with obesity supports the use of ephedrine for fat loss, no studies have been done on athletes. The few studies of cocaine and exercise suggest that little to no performance gains are incurred from cocaine use. Moreover, the sense of euphoria may provide the illusion of better performance when, in actuality, performance was not improved or was impaired. beta-Blockers have been found to reduce heart rate and tremor and to improve performance in sports that are not physiologically challenging but require accuracy (e.g. pistol shooting). However, there is evidence that some individuals may be high responders to beta-blockers to the extent that their heart rate response is so blunted as to impair performance. Although equivocal, several studies have reported that anabolic-androgenic steroids increase muscle size and strength. However, most studies are not well controlled and use insufficient drug doses. One recent well controlled study did find an increase in muscle mass and strength with supraphysiological doses, and the improvements were greater in participants who were also resistance training. There is little information available on the effects of growth hormone on muscle mass or performance in athletes, although data suggest that growth hormone administration does not increase muscle protein synthesis. beta 2-Agonists, such as clenbuterol and salbutamol, when administered orally appear to improve muscular strength due to their potential role in increasing muscle mass. However, studies have not been done using athletes. Diuretics results in a loss of body water and hence bodyweight that can be advantageous for sports with strict bodyweight classifications. There is insufficient evidence on possible performance decrements in the field that could result from dehydration induced by the diuretics. Overall, the most significant concern in studies of drug use is the large inter-individual variability in responses to a drug. Further studies are needed to understand why some individuals are more responsive than others and to assess whether the responses are consistent for a given individual. Most studies of drug effectiveness have not used athletes. The effectiveness of many drugs may be reduced in highly trained athletes because there is a lower margin for improvement.
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PMID:Drugs and sport. Research findings and limitations. 942 62

Muscle catabolism is a characteristic metabolic response to sepsis, severe infection, and injury. In patients with severe and protracted sepsis, the catabolic response results in muscle wasting and fatigue, which may adversely affect the outcome in these patients. An understanding of the regulation of muscle protein breakdown during sepsis and the mechanisms involved is important from a clinical standpoint and is essential for the development of new therapeutic modalities to prevent protein loss from muscle tissue. Studies in septic patients and experimental animals have provided evidence that the myofibrillar proteins actin and myosin are particularly sensitive to the effects of sepsis. Among the factors that regulate muscle protein breakdown during sepsis, the proinflammatory cytokines tumor necrosis factor and interleukin-1, together with glucocorticoids, are the principal mediators. Intracellular protein breakdown is regulated by multiple proteolytic pathways. Among these, the energy-ubiquitin-dependent pathway accounts for a major portion of muscle protein breakdown during sepsis. The development of specific proteasome inhibitors may make it possible in the future to target the molecular mechanisms of sepsis-induced increase in muscle proteolysis. Such treatment may prove an important avenue to reduce the metabolic cost in patients with severe infection or sepsis.
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PMID:Sepsis: stimulation of energy-dependent protein breakdown resulting in protein loss in skeletal muscle. 945 37

Six amino acids are metabolized in resting muscle. They are leucine, isoleucine, valine, asparagine, aspartate, and glutamate. These amino acids provide the amino groups and probably the ammonia required for synthesis of glutamine and alanine, which are released in excessive amounts in the postabsorptive state and during ingestion of a protein-containing meal. Only leucine and part of the isolecine molecule can be oxidized in muscle as they are converted to acetyl-CoA. The other carbon skeletons are used solely for de novo synthesis of TCA-cycle intermediates and glutamine. The carbon atoms of the released alanine originate primarily from glycolysis of blood glucose and from muscle glycogen (about half each in resting conditions). After consumption of a protein-containing meal, BCAA and glutamate are taken up by muscle and their carbon skeletons are used for de novo synthesis of glutamine. About half of the glutamine released from muscle originates from glutamate taken up from the blood, both after overnight starvation, after prolonged starvation, and after consumption of a mixed meal. Glutamine produced by muscle is an important fuel and regulator of DNA and RNA synthesis in mucosal cells and immune system cells, and fulfils several other important functions in human metabolism. The alanine aminotransferase reaction functions to establish and maintain high concentrations of TCA-cycle intermediates in muscle during the first 10 min of exercise. The increase in concentration of TCA-cycle intermediates probably is needed to increase the flux of the TCA-cycle and meet the increased energy demand of exercise. A gradual increase in leucine oxidation subsequently leads to a carbon drain on the TCA-cycle in glycogen-depleted muscles, and may thus reduce the maximal flux in the TCA-cycle and lead to fatigue. Deamination of amino acids and glutamine synthesis present alternative anaplerotic mechanisms in glycogen-depleted muscles, but only allow exercise at 40-50% of Wmax. One-leg exercise leads to the net breakdown of muscle protein. The liberated amino acids are used for synthesis of TCA-cycle intermediates and glutamine. Today, the importance of this process in endurance exercise in the field (running or cycling) in athletes who ingest carbohydrates is not clear. It is proposed that the maximal flux in the TCA-cycle is reduced in glycogen-depleted muscles due to insufficient TCA-cycle anaplerosis, and that this presents a limitation for the maximal rate of fatty acid oxidation. Interactions between the amino acid pool and the TCA-cycle are suggested to play a central role in the energy metabolism of the exercising muscle.
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PMID:Muscle amino acid metabolism at rest and during exercise: role in human physiology and metabolism. 969 93

Muscle proteins turn over slowly and there are minimal diurnal changes in the size of the muscle protein pool in response to feeding and fasting. Nitrogen balance and tracer studies indicate that protein oxidation and net protein breakdown (degradation--synthesis) is not increased during dynamic exercise at intensities of < or = 70% VO2max. An imbalance between muscle protein synthesis and degradation does exist during one leg knee extensor exercise and during two legged cycling in patients with glycogen phosphorylase deficiency. In these latter cases amino acids liberated from the protein pool are used for synthesis of TCA-cycle intermediates and glutamine. Six amino acids are metabolized in resting muscle: leucine, isoleucine, valine, asparagine, aspartate and glutamate. Only leucine and part of the isoleucine molecule can be converted to acetylCoA and oxidized. The carbon skeleton of the other amino acids is used for synthesis of TCA-cycle intermediates and glutamine. The six amino acids provide the amino groups and the ammonia for synthesis of glutamine and alanine, which are released by muscle in excessive amounts. About half of the glutamine release from muscle originates from glutamate taken up from the blood. Glutamine produced by muscle is an important fuel and regulator of DNA and RNA synthesis in mucosal cells and immune system cells and fulfils several other important functions in human metabolism. The alanine aminotransferase reaction functions to establish and maintain high concentrations of TCA-cycle intermediates and a high TCA cycle flux in the first minutes of exercise. A gradual increase in leucine oxidation subsequently leads to a carbon drain on the TCA-cycle in glycogen depleted muscles and may thus reduce the maximal flux in the TCA-cycle and lead to fatigue. Deamination of amino acids and glutamine synthesis present alternative anaplerotic mechanisms in glycogen depleted muscles but only allow exercise at 40-50% of Wmax. It is proposed that the maximal flux in the TCA-cycle is reduced in glycogen depleted muscles due to insufficient TCA-cycle anaplerosis and that this presents a limitation for the maximal rate of fatty acid oxidation. Interactions between the amino acid pool and the TCA-cycle thus seem to play a central role in the energy metabolism of the exercising muscle.
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PMID:Protein and amino acid metabolism in human muscle. 978 36

This study evaluated the influence of dystonia musculorum (dt) mutation, characterized by spinocerebellar fibers degeneration, on cardiac and skeletal muscles: one respiratory (diaphragm, Dia), three masticatory (anterior temporalis, AT; masseter superficialis, MS; and anterior digastric, AD), one hindlimb (soleus, S), tongue (T), and one cardiac (ventricle, V). Body and muscle weight, muscle protein content, and myosin heavy chain (MHC) isoforms relative expression were then compared in dt mutant mice and in normal mice, according to sex. Male body and muscle weight was always greater than that of females, but there was no specific muscle difference in females. dt mutant mice showed a reduced whole body growth but no specific muscle atrophy, as well as a global decrease in muscle protein content that made muscles more fragile. dt mutation induced a global reduction of muscle protein concentration, whereas a general influence of sex could not be disclosed. Concerning MHC relative composition, all the muscles were fast-twitch: Dia, AT, MS, AD, S, and T expressed predominantly the fast type 2 MHC isoforms, whereas V contained only MHC alpha, also a fast MHC. Female muscles were slower than male muscles, except for S, which was faster. However, classification of muscles in terms of shortening velocity was very different in normal males and females. In other respects, dt mutant muscles were slower and consequently more fatigue resistant than normal, except for S, which became faster and less fatigue resistant. dt mutation exhibits then a specific effect on this continually active postural muscle. In the other muscles, global increased fatigue resistance could constitute an adaptive response to work requirements modifications linked to the muscle damage. It should be noted that a developmental MHC (neonatal) was present in female dt AD. Innervation, which influences muscle structure, is altered in dt mutant and could be another causal factor of the fast-to-slow MHC switches. It appears that dystonin, the dt gene product, is very important in maintaining the structural integrity of both cardiac and skeletal muscle and in its absence, the muscle becomes more fragile and is damaged by modified activity.
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PMID:Dystonia musculorum mutation and myosin heavy chain expression in skeletal and cardiac muscles. 1038 Dec 65

Although current research suggests that individuals involved in either high-intensity resistance or endurance exercise may have an increased need for dietary protein, the available research is either equivocal or negative relative to the ergogenic effects of supplementation with individual amino acids. Although some research suggests that the induction of hyperaminoacidemia via intravenous infusion of a balanced amino acid mixture may induce an increased muscle protein synthesis after exercise, no data support the finding that oral supplementation with amino acids, in contrast to dietary protein, as the source of amino acids is more effective. Some well-controlled studies suggest that aspartate salt supplementation may enhance endurance performance, but other studies do not, meriting additional research. Current data, including results for several well-controlled studies, indicated that supplementation with arginine, ornithine, or lysine, either separately or in combination, does not enhance the effect of exercise stimulation on either hGH or various measures of muscular strength or power in experienced weightlifters. Plasma levels of BCAA and tryptophan may play important roles in the cause of central fatigue during exercise, but the effects of BCAA or tryptophan supplementation do not seem to be effective ergogenics for endurance exercise performance, particularly when compared with carbohydrate supplementation, a more natural choice. Although glutamine supplementation may increase plasma glutamine levels, its effect on enhancement of the immune system and prevention of adverse effects of the overtraining syndrome are equivocal. Glycine, a precursor for creatine, does not seem to possess the ergogenic potential of creatine supplementation. Research with metabolic by-products of amino acid metabolism is in its infancy, and current research findings are equivocal relative to ergogenic applications. In general, physically active individuals are advised to obtain necessary amino acids through consumption of natural, high-quality protein foods.
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PMID:Facts and fallacies of purported ergogenic amino acid supplements. 1041 Aug 46

Mammalian skeletal muscle shows an enormous variability in its functional features such as rate of force production, resistance to fatigue, and energy metabolism, with a wide spectrum from slow aerobic to fast anaerobic physiology. In addition, skeletal muscle exhibits high plasticity that is based on the potential of the muscle fibers to undergo changes of their cytoarchitecture and composition of specific muscle protein isoforms. Adaptive changes of the muscle fibers occur in response to a variety of stimuli such as, e.g., growth and differentition factors, hormones, nerve signals, or exercise. Additionally, the muscle fibers are arranged in compartments that often function as largely independent muscular subunits. All muscle fibers use Ca(2+) as their main regulatory and signaling molecule. Therefore, contractile properties of muscle fibers are dependent on the variable expression of proteins involved in Ca(2+) signaling and handling. Molecular diversity of the main proteins in the Ca(2+) signaling apparatus (the calcium cycle) largely determines the contraction and relaxation properties of a muscle fiber. The Ca(2+) signaling apparatus includes 1) the ryanodine receptor that is the sarcoplasmic reticulum Ca(2+) release channel, 2) the troponin protein complex that mediates the Ca(2+) effect to the myofibrillar structures leading to contraction, 3) the Ca(2+) pump responsible for Ca(2+) reuptake into the sarcoplasmic reticulum, and 4) calsequestrin, the Ca(2+) storage protein in the sarcoplasmic reticulum. In addition, a multitude of Ca(2+)-binding proteins is present in muscle tissue including parvalbumin, calmodulin, S100 proteins, annexins, sorcin, myosin light chains, beta-actinin, calcineurin, and calpain. These Ca(2+)-binding proteins may either exert an important role in Ca(2+)-triggered muscle contraction under certain conditions or modulate other muscle activities such as protein metabolism, differentiation, and growth. Recently, several Ca(2+) signaling and handling molecules have been shown to be altered in muscle diseases. Functional alterations of Ca(2+) handling seem to be responsible for the pathophysiological conditions seen in dystrophinopathies, Brody's disease, and malignant hyperthermia. These also underline the importance of the affected molecules for correct muscle performance.
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PMID:Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. 1089 34

We examined the effect of an isolated bout of maximal tolerated passive stretch on fractional muscle protein synthetic rate in human soleus muscle. Eight healthy males performed two separate trials with the same leg: one session of passive stretch and one of intermittent active isometric contraction at a force equivalent to that which occurred during the passive stretch trial. This force was approximately 40% of maximum voluntary contraction force and produced volitional fatigue in approximately 27 min. Intermittent passive stretch, for the same duration, elicited a 6.1 degrees increase in joint angle (P<.0005) with silent electromyography. Fractional protein synthetic rate from experimental and control soleus in each trial was assessed from biopsy samples over the period 10-22 hr postexercise by the incorporation rate of L-[1-13C] leucine into muscle. Protein synthesis was elevated in the soleus of the exercised leg following the active contraction trial by 49% (P<.05) but not following the passive stretch trial. Results indicate that a single bout of maximal passive stretch does not significantly elevate fractional muscle protein synthetic rate in humans and thus suggests that muscle stretch per se is not the stimulus for the muscle hypertrophy that occurs with resistance training.
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PMID:The effects of acute passive stretch on muscle protein synthesis in humans. 1093 34

This study evaluated the influence of Lurcher mutation, characterized by degeneration of cerebellar Purkinje cells, granule cells, and inferior olive neurons, on cardiac and skeletal muscles: one respiratory (diaphragm, Dia), three masticatory (anterior temporalis, AT; masseter superficialis, MS and anterior digastric, AD), one hind limb (soleus, S), entire tongue (T), and one cardiac (ventricle, V) muscles. Body and muscle weight, muscle protein content, and myosin heavy chain (MHC) isoforms relative expression were then compared in Lurcher mutant mice vs. normal, according to sex. Male body weight was always greater than female one, but there was no specific muscle difference in females, except for T relative weight which was greater in normal females. Muscle protein concentration was greater in normal males except for AD and T in which it was lower. Lurcher mutant mice showed a reduced whole body growth but no specific muscle atrophy (except in male AT), and a global decrease in muscle protein content which made muscles more fragile (except in female Dia and male T, in which it was greater). Lurcher mutation induced a global reduction of muscle protein concentration whereas a general influence of sex could not be disclosed. Concerning MHC relative composition, all the muscles were fast-twitch: Dia, AT, MS, AD, S, and T predominantly expressed the fast type 2 MHC isoforms, except female S, whereas V contained only MHC alpha, also a fast MHC. Female muscles were slower than male ones and classification of muscles in terms of shortening velocity was comparable in normal male and female. In other respects, male Lurcher mutant muscles were slower and consequently more fatigue resistant than normal, except T which became faster and less fatigue resistant. On the contrary, in female mutants, only the Dia was slower than normal one, MS and AD were comparable to normal ones and finally, AT, S, and T were faster than normal ones. It should be noted that a developmental MHC (neonatal) was present in Lurcher AD. Motor control, which influences muscle structure, is altered in Lurcher mutant and could be one of the causal factor of the fast-to-slow MHC switches observed in some mutant muscles. It seems therefore that cerebellar Purkinje cells, granule cells, and inferior olive neurons are very important in maintaining the structural integrity of both cardiac and skeletal muscle, and their degeneration is accompanied by important muscles modifications. J. Cell. Biochem. Suppl. 36: 222-231, 2001.
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PMID:Influence of the Lurcher mutation on myosin heavy chain expression in skeletal and cardiac muscles. 1145 87

Cachexia, a wasting condition often seen in advanced cancer, is often confused with anorexia but they are two separate conditions. It is evident that cachexia frequently leads to anorexia but anorexia alone cannot cause cachexia. The cachexia syndrome is weight loss with a specific cause--the action of cytokines, chemical messengers that are produced both by the body in response to the tumour and by the tumour to ensure its growth and spread. Treatment of cachexia is very difficult. Drugs to improve appetite have little effect, however, supplementing the diet with fish oils and vitamin E seems to be beneficial. Increasing a patient's level of exercise, even if bed-bound, does seem to have a positive effect and helps to synthesize skeletal muscle protein and delay the ravages of cachexia. Increasing exercise also has a positive effect on fatigue levels, a side-effect of cachexia.
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PMID:Understanding cachexia and excessive weight loss in cancer. 1630 22


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