Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clenbuterol has been shown to ameliorate denervation-induced atrophy and, therefore, clearly has therapeutic potential in the treatment of muscle wasting conditions in man. Previous studies have used dosages in rats which would be unacceptable in clinical practice, but the present results show that denervated muscle has a greater sensitivity to the drug than innervated or cardiac muscle. Fiber hypertrophy and an increase in protein and RNA content could be observed in denervated muscles but not in innervated muscles at a dose of 10 micrograms/kg body weight. When considered on a metabolic body weight basis, the effective dose in rats and the "safe" dose in man are surprisingly comparable. The observations imply that there is good reason to suppose that clenbuterol could be effective in ameliorating similar wasting conditions in man.
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PMID:Denervation increases clenbuterol sensitivity in muscle from young rats. 154 39

The degree of DNA-polyploidy of cardiac muscle cells was investigated by cytofluorometry in 4 cases of progressive muscular dystrophy (DMP) and 2 cases of myotonic dystrophy (DM), and the results were compared with those for non-dystrophic hearts of normal or increased weight. The heart muscle cells from all patients with these forms of dystrophy showed marked nuclear DNA hyperploidy reaching 16c, irrespective of cardiac hypertrophy or atrophy. In the non-dystrophic group, DNA hypertrophy corresponding to that of dystrophy was only detected in cases of marked cardiac hypertrophy exceeding a weight of 400 g. The wasting of the respiratory musculature, deformity of the thorax and cardiac muscular atrophy appeared to be the principal factors causing DNA polyploidy in patients with muscular dystrophy.
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PMID:Cytofluorometric determination of nuclear DNA in heart muscles of patients with muscular dystrophy. 253 66

The cardiovascular status of severely malnourished children was characterized before, during, and after nutritional rehabilitation. In most children with third-degree malnutrition, cardiac mass was decreased on admission to the hospital and recovered subsequent to nutritional therapy. All children had echocardiographic and Doppler measurements indicative of impaired ventricular function which significantly improved during the course of hospitalization, as evidenced in part by the change in fractional shortening (P = 0.015), mean velocity of circumferential fiber shortening (P = 0.038), and systolic time interval (P = 0.030). We conclude that children with primary third-degree malnutrition not only have cardiac muscle wasting, but also have inherent ventricular dysfunction as the result of severe malnutrition that responds to nutritional therapy. Particular care with fluid administration is imperative in the first week of therapy, when heart function is the most compromised.
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PMID:Cardiac function in malnourished children. 819 89

Ryanodine (RYA) at a low concentration (several tens of nM) is known to selectively bind to Ca2+ release channels in sarcoplasmic reticulum (SR) and to fix them open. The present study was designed to investigate the effects of the selective change in Ca2+ release channel activity on cardiac mechanoenergetics as a model of Ca(2+)-leaky SR observed in pathological hearts. We analyzed the negative inotropic effect of RYA at a low concentration (up to 30 +/- 13 nM) on left ventricular (LV) mechanoenergetics using frameworks of LV Emax (a contractility index) and the myocardial oxygen consumption (LV VO2)-systolic pressure-volume area (PVA) (a measure of total mechanical energy) relation in 11 isolated, blood-perfused dog hearts. RYA significantly decreased Emax by 42%, whereas PVA-independent VO2 remained disproportionately high (93% of control). This oxygen-wasting effect of RYA was quite different from ordinary inotropic drugs, which alter Emax and PVA-independent VO2 proportionally. The present result suggests that RYA suppresses force generation of cardiac muscle for a given amount of total sequestered Ca2+ by SR in a similar way to myocardial ischemia and stunning. We speculate about the underlying mechanism that RYA makes SR leaky for Ca2+ and thereby wastes energy for Ca2+ handling by SR.
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PMID:Ryanodine wastes oxygen consumption for Ca2+ handling in the dog heart. A new pathological heart model. 839 87

The heart is known for its ability to produce energy from fatty acids (FA) because of its important beta-oxidation equipment, but it can also derive energy from several other substrates including glucose, pyruvate, and lactate. The cardiac ATP store is limited and can assure only a few seconds of beating. For this reason the cardiac muscle can adapt quickly to the energy demand and may shift from a 100% FA-derived energy production (after a lipid-rich food intake) or any balanced situation (e.g., diabetes, fasting, exercise). These situations are not similar for the heart in terms of oxygen requirement because ATP production from glucose is less oxygen-consuming than from FA. The regulation pathways for these shifts, which occur in physiologic as well as pathologic conditions (ischemia-reperfusion), are not yet known, although both insulin and pyruvate dehydrogenase activation are clearly involved. It becomes of strategic importance to clarify the pathways that control these shifts to influence the oxygen requirement of the heart. Excess FA oxidation is closely related to myocardial contraction disorders characterized by increased oxygen consumption for cardiac work. Such an increased oxygen cost of cardiac contraction was observed in stunned myocardium when the contribution of FA oxidation to oxygen consumption was increased. In rats, an increase in n-3 polyunsaturated FA in heart phospholipids achieved by a fish-oil diet improved the recovery of pump activity during postischemic reperfusion. This was associated with a moderation of the ischemia-induced decrease in mitochondrial palmitoylcarnitine oxidation. In isolated mitochondria at calcium concentrations close to that reported in ischemic cardiomyocytes, a futile cycle of oxygen wastage was reported, associated with energy wasting (constant AMP production). This occurs with palmitoylcarnitine as substrate but not with pyruvate or citrate. The energy wasting can be abolished by CoA-SH and other compounds, but not the oxygen wasting. Again, the calcium-induced decrease in mitochondrial ADP/O ratio was reduced by increasing the n-3 polyunsaturated FA in the mitochondrial phospholipids. These data suggest that in addition to the amount of circulating lipids, the quality of FA intake may contribute to heart energy regulation through the phospholipid composition. On the other hand, other intervention strategies can be considered. Several studies have focused on palmitoylcarnitine transferase I to achieve a reduction in beta-oxidation. In a different context, trimetazidine was suggested to exert its anti-ischemic effect on the heart by interfering with the metabolic shift, either at the pyruvate dehydrogenase level or by reducing the beta-oxidation. Further studies will be required to elucidate the complex system of heart energy regulation and the mechanism of action of potentially efficient molecules.
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PMID:Fatty acid oxidation in the heart. 889 66

Dystrophin is a cytoskeletal protein of muscle fibers; its loss in humans leads to Duchenne muscular dystrophy, an inevitably fatal wasting of skeletal and cardiac muscle. mdx mice also lack dystrophin, but are only mildly dystrophic. Utrophin, a homolog of dystrophin, is confined to the postsynaptic membrane at skeletal neuromuscular junctions and has been implicated in synaptic development. However, mice lacking utrophin show only subtle neuromuscular defects. Here, we asked whether the mild phenotypes of the two single mutants reflect compensation between the two proteins. Synaptic development was qualitatively normal in double mutants, but dystrophy was severe and closely resembled that seen in Duchenne. Thus, utrophin attenuates the effects of dystrophin deficiency, and the double mutant may provide a useful model for studies of pathogenesis and therapy.
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PMID:Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. 928 52

Following an outbreak of wobbly possum disease in a colony of brush tail possums (Trichosurus vulpecula), the disease was established experimentally in captive possums by inoculating the animals intraperitoneally with tissue homogenates. Crude tissue homogenates of liver remained infectious after freezing at -75 degrees C or filtration through a 0.22 micron filter. The disease was characterised by docility, incoordination, loss of balance and wasting. Fifteen of 16 infected animals had to be euthanased owing to the severity of clinical signs. Cachexia was the only change observed postmortem. Histology revealed widespread perivascular infiltrations with plasma cells and lymphocytes which were severe in the liver and kidney and moderate to mild in a variety of other tissues, including skeletal and cardiac muscle. Changes in the brain consisted of a mild to moderate mononuclear perivascular cuffing. Most of the animals had small to large numbers of circulating nucleated red blood cells and eosinopenia when they were euthanased. There was a consistent decrease in serum albumin concentration and an increase in serum globulins, which resulted in a decreased albumin:globulin ratio. Virus-like particles were observed in preparations of liver from two animals; they appeared to be spherical or icosahedral and were 45 nm in diameter.
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PMID:Pathological studies of wobbly possum disease in New Zealand brushtail possums (Trichosurus vulpecula). 930 Oct 11

The ubiquitin-proteasome system is thought to play a major role in normal muscle protein turnover and to contribute to diabetes-induced protein wasting in skeletal muscle. However, its importance in cardiac muscle is not clear. We measured heart muscle mRNA for ubiquitin and for the C2 and C8 proteasomal subunits, the amount of free ubiquitin and the proteasome chymotrypsin-like proteolytic activity in control and diabetic rats. Results were compared to those in skeletal muscle (rectus). Heart ubiquitin, C2 and C8 subunit mRNA and proteolytic activity were significantly greater than in skeletal muscle (P </= 0.05). This suggests that the ubiquitin proteasomal pathway may also be important for normal heart muscle turnover. Diabetes increased ubiquitin mRNA by approximately 50% in heart (P < 0.03) and by approximately 100% in skeletal muscle (P < 0.005). It remained high after 3 days of insulin treatment in both tissues. C2 and C8 subunit mRNA did not change with diabetes or insulin treatment. Diabetes did not change the amount of free ubiquitin or the proteasomal (lactacystin-inhibitable) chymotrypsin-like peptidase activity in heart or skeletal muscle. In conclusions, gene expression for several components of the ubiquitin-proteasome proteolytic pathway is significantly higher in cardiac than in skeletal muscle, as is the proteasome chymotrypsin-like peptidase activity. Diabetes increases the expression of ubiquitin but not C2 or C8 subunit mRNA, nor does it significantly alter the amount of free ubiquitin or the proteasome chymotrypsin-like peptidase activity. The rate-limiting step of enhanced protein degradation in diabetic rat heart and skeletal muscle may be located at ubiquitin conjugation and/or its binding to proteasome, not at the ubiquitin availability or the proteasome itself.
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PMID:The ubiquitin-proteasome proteolytic pathway in heart vs skeletal muscle: effects of acute diabetes. 1102 19

The majority of symptomatic patients with congestive heart failure have been shown to be significantly malnourished. Myocardial and skeletal muscle energy reserves are also diminished. Total daily energy expenditure in these patients is less than that in control individuals, and high protein-calorie feeds do not reverse the abnormalities; thus, the wasting that occurs in patients with congestive heart failure is metabolic rather than because of negative protein-calorie balance. Several specific deficiencies have been found in the failing myocardium: a reduction in the content of L-carnitine, coenzyme Q10, creatine and thiamine, nutrient cofactors that are important for myocardial energy production; a relative deficiency of taurine, an amino acid that is integral to the modulation of intracellular calcium levels; and an increase in myocardial oxidative stress, and a reduction of both endogenous and exogenous antioxidant defences. In addition, these processes may influence skeletal muscle metabolism and function. Cellular nutritional requirements conditioned by metabolic abnormalities in heart failure are important considerations in the pathogenesis of the skeletal and cardiac muscle dysfunction. A comprehensive restoration of adequate myocyte nutrition would seem to be essential to any therapeutic strategy designed to benefit patients suffering from this disease.
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PMID:Conditioned nutritional requirements and the pathogenesis and treatment of myocardial failure. 1108 25

Here, we describe a novel spontaneous autosomal recessive mutation in the mouse that is characterized by skeletal and cardiac muscle degeneration. We have named this mutant degenerating muscle (dmu). At birth, mutant mice are indistinguishable from their normal littermates. Thereafter, the disease progresses rapidly and a phenotype is first observed at approximately 11 days after birth; the dmu mice are weak and have great difficulty in moving. The principal cause of the lack of mobility is muscle atrophy and wasting in the hindquarters. Affected mice die at or around the time of weaning of unknown causes. Histopathological observations and ultrastructural analysis revealed muscle degeneration in both skeletal and cardiac muscle, but no abnormalities in sciatic nerves. Using linkage analysis, we have mapped the dmu locus to the distal portion of mouse chromosome 15 in a region syntenic to human chromosome 12q13. Interestingly, scapuloperoneal muscular dystrophy (SPMD) in humans has been linked to this region. SPMD patients with associated cardiomyopathy have also been described in the past. Initial analysis of candidate genes on mouse chromosome 15 reveal that although intact transcripts for Scn8a, the gene encoding the sodium channel 8a subunit, are present in dmu mice, their levels are dramatically reduced. Furthermore, genetic complementation crosses between dmu and med (mutation in Scn8a) mice revealed that they are allelic. Our results suggest that at least a portion of the dmu phenotype is caused by a down-regulation of Scn8a, making dmu a new allele of Scn8a.
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PMID:Pathological and genetic analysis of the degenerating muscle (dmu) mouse: a new allele of Scn8a. 1153 91


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