[Skeletal muscle dysfunction in COPD. Cell mechanisms. A.G.N].
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Apoptosis↗
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Results for “Skeletal muscle dysfunction”
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Temperature-dependent skeletal muscle dysfunction in rats with congestive heart failure.
Abnormalities in the excitation-contraction coupling of slow-twitch muscle seem to explain the slowing and increased fatigue observed in congestive heart failure (CHF). However, it is not known which elements of the excitation-contraction coupling might be affected. We hypothesize that the temperature sensitivity of contractile properties of the soleus muscle might be altered in CHF possibly because of alterations of the temperature sensitivity of intracellular Ca(2+) handling. We electrically stimulated the in situ soleus muscle of anesthetised rats that had 6-wk postinfarction CHF using 1 and 50 Hz and using a fatigue protocol (5-Hz stimulation for 30 min) at 35, 37, and 40 degrees C. Ca(2+) uptake and release were measured in sarcoplasmic reticulum vesicles at various temperatures. Contraction and relaxation rates of the soleus muscle were slower in CHF than in sham at 35 degrees C, but the difference was almost absent at 40 degrees C. The fatigue protocol revealed that force development was more temperature sensitive in CHF, whereas contraction and relaxation rates were less temperature sensitive in CHF than in sham. The Ca(2+) uptake and release rates did not correlate to the difference between CHF and sham regarding contractile properties or temperature sensitivity. In conclusion, the discrepant results regarding altered temperature sensitivity of contraction and relaxation rates in the soleus muscle of CHF rats compared with Ca(2+) release and uptake rates in vesicles indicate that the molecular cause of slow-twitch muscle dysfunction in CHF is not linked to the intracellular Ca(2+) cycling.
Adenosine Triphosphate↗
Skeletal muscle dysfunction in chronic renal failure: effects of exercise.
A number of chronic illnesses such as renal failure (CRF), obstructive pulmonary disease, and congestive heart failure result in a significant decrease in exercise tolerance. There is an increasing awareness that prescribed exercise, designed to restore some level of physical performance and quality of life, can be beneficial in these conditions. In CRF patients, muscle function can be affected by a number of direct and indirect mechanisms caused by renal disease as well as various treatment modalities. The aims of this review are twofold: first, to briefly discuss the mechanisms by which CRF negatively impacts skeletal muscle and, therefore, exercise capacity, and, second, to discuss the available data on the effects of programmed exercise on muscle function, exercise capacity, and various other parameters in CRF.
Exercise Therapy↗
Skeletal muscle dysfunction in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a major health care problem. Formerly mainly a disease of men, women are increasingly frequently afflicted. In many of these patients, exercise intolerance is the chief complaint. Few effective therapies are available. In recent years, dysfunction of the muscles of ambulation has been identified as a source of a portion of the exercise intolerance these patients experience, and this dysfunction has been shown to be, at least in part, remediable. Mechanisms inducing muscle dysfunction include disuse atrophy, malnutrition, low levels of anabolic steroids, and myopathy from corticosteroid use. Endurance exercise training has been conclusively demonstrated to improve exercise tolerance in COPD. Recent studies suggest that strength training is beneficial as well. A new frontier of therapy for muscle dysfunction in COPD is the use of anabolic hormones. Testosterone supplementation has been shown to increase muscle mass and strength in both hypogonadal and eugonadal healthy men. Low-dose testosterone supplementation is being considered for use in postmenopausal women. Though short-term administration of testosterone in moderate doses seems to be well tolerated in both men and women, further studies are required before safety and effectiveness can be established for routine use in COPD patients.
Androgens↗
A specific skeletal muscle dysfunction in iron deficiency.
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Anemia, Hypochromic↗
Burn injury causes mitochondrial dysfunction in skeletal muscle.
Severe burn trauma is generally followed by a catabolic response that leads to muscle wasting and weakness affecting skeletal musculature. Here, we perform whole-genome expression and in vivo NMR spectroscopy studies to define respectively the full set of burn-induced changes in skeletal muscle gene expression and the role of mitochondria in the altered energy expenditure exhibited by burn patients. Our results show 1,136 genes differentially expressed in a mouse hind limb burn model and identify expression pattern changes of genes involved in muscle development, protein degradation and biosynthesis, inflammation, and mitochondrial energy and metabolism. To assess further the role of mitochondria in burn injury, we performed in vivo (31)P NMR spectroscopy on hind limb skeletal muscle, to noninvasively measure high-energy phosphates and the effect of magnetization transfer on inorganic phosphate (P(i)) and phosphocreatine (PCr) resonances during saturation of gammaATP resonance, mediated by the ATP synthesis reactions. Although local burn injury does not alter high-energy phosphates or pH, apart from PCr reduction, it does significantly reduce the rate of ATP synthesis, to further implicate a role for mitochondria in burn trauma. These results, in conjunction with our genomic results showing down-regulation of mitochondrial oxidative phosphorylation and related functions, strongly suggest alterations in mitochondrial-directed energy expenditure reactions, advancing our understanding of skeletal muscle dysfunction suffered by burn injury patients.
Adenosine Triphosphate↗
Expression of MCT1 and MCT4 in a patient with mitochondrial myopathy.
Mitochondrial myopathies (MM) are characterized by alterations in oxidative phosphorylation. The resultant increase in glycolytic flux produces a variable lactic acidosis. Intracellular acidification can induce both metabolic and, in the case of skeletal muscle, contractile dysfunction. Skeletal muscle lactate transporters have recently been identified which include both monocarboxylate transporter 1 (MCT1) and 4 (MCT4). Lactate import into oxidative skeletal muscle appears to be catalyzed by MCT1, whereas its extrusion from glycolytic fibers may be mediated by MCT4. We describe the expression of these isoforms in a patient with MM as compared to controls (n = 5). MCT4 content was 86% (>3 SD) higher in the patient with MM, whereas MCT1 content was less markedly elevated (47%), as compared to controls. These findings support previous work suggesting that the major role of MCT4 is to defend intracellular pH by extruding lactate and H(+) to the interstitium. The role of MCT1 in MM is less clear.
Aged↗
Hypoxia-induced skeletal muscle fiber dysfunction: role for reactive nitrogen species.
Hypoxia impairs skeletal muscle function, but the precise mechanisms are incompletely understood. In hypoxic rat diaphragm muscle, generation of peroxynitrite is elevated. Peroxynitrite and other reactive nitrogen species have been shown to impair contractility of skinned muscle fibers, reflecting contractile protein dysfunction. We hypothesized that hypoxia induces contractile protein dysfunction and that reactive nitrogen species are involved. In addition, we hypothesized that muscle reoxygenation reverses contractile protein dysfunction. In vitro contractility of rat soleus muscle bundles was studied after 30 min of hyperoxia (Po2 approximately 90 kPa), hypoxia (Po2 approximately 5 kPa), hypoxia + 30 microM N(G)-monomethyl-L-arginine (L-NMMA, a nitric oxide synthase inhibitor), hyperoxia + 30 microM L-NMMA, and hypoxia (30 min) + reoxygenation (15 min). One part of the muscle bundle was used for single fiber contractile measurements and the other part for nitrotyrosine detection. In skinned single fibers, maximal Ca2+-activated specific force (Fmax), fraction of strongly attached cross bridges (alphafs), rate constant of force redevelopment (ktr), and myofibrillar Ca2+ sensitivity were determined. Thirty minutes of hypoxia reduced muscle bundle contractility. In the hypoxic group, single fiber Fmax, alphafs, and ktr were significantly reduced compared with hyperoxic, L-NMMA, and reoxygenation groups. Myofibrillar Ca2+ sensitivity was not different between groups. Nitrotyrosine levels were increased in hypoxia compared with all other groups. We concluded that acute hypoxia induces dysfunction of skinned muscle fibers, reflecting contractile protein dysfunction. In addition, our data indicate that reactive nitrogen species play a role in hypoxia-induced contractile protein dysfunction. Reoxygenation of the muscle bundle partially restores bundle contractility but completely reverses contractile protein dysfunction.
Animals↗
The temporal relationship between endothelial cell dysfunction and skeletal muscle damage after ischemia and reperfusion.
Reperfusion-induced vascular endothelial cell dysfunction may exacerbate skeletal muscle damage after an ischemic insult. Although concurrent endothelial and skeletal muscle injury has been documented after ischemia and reperfusion, their temporal relationship has not been well characterized. An isolated rat hindlimb model was used to measure the effect of progressive ischemia and reperfusion on both endothelial cell function and skeletal muscle damage. Endothelial cell dysfunction as reflected by changes in permeability was measured by protein clearance techniques with use of albumin labeled with iodine 125 (125I-albumin). Skeletal muscle damage was assessed by tissue uptake of technetium 99m pyrophosphate (99mTc-pyrophosphate). The soleus muscle was used for evaluation of endothelial and skeletal muscle damage throughout the study. Significant increases in vascular permeability preceded skeletal muscle damage. The protein leak index increased after 60 minutes of ischemia and reperfusion (7.5 +/- 1.2 vs 4.1 +/- 0.9 control), whereas the muscle injury index did not change until 120 minutes of ischemia and 60 minutes of reperfusion (10.5 +/- 0.6 vs 4.5 +/- 0.5 control). Significant graded increases in both indexes were noted with longer intervals of ischemia. Electron microscopy revealed ultrastructural evidence of endothelial and skeletal muscle damage after 120 minutes of ischemia and 60 minutes of reperfusion but not after 60 minutes of ischemia and reperfusion. These studies indicate that microvascular injury precedes skeletal muscle damage after ischemia and reperfusion. This temporal relationship may have important implications in designing strategies to minimize ischemia-reperfusion injury.
Analysis of Variance↗
[Cardiac dysfunction in female gene carriers of Duchenne muscular dystrophy].
Cardiac dysfunction and its correlation with skeletal muscle dysfunction were examined in 16 definite female gene carriers of Duchenne muscular dystrophy (DMD). Five out of 16 carriers (31.3%) had cardiac symptoms and 8 carriers (50.0%) showed an increased cardio-thoracic ratio on chest X-ray. Electrocardiographic abnormalities including a high R:S ratio (> or = 1.0) in the V1 lead, deep Q wave (> 3 mm) in the I, II, aVL, V5, and V6 leads, complete right bundle branch block and premature ventricular beats, were observed in 9 carriers (56.3%). On echocardiographic examination, an increase in the end-diastolic dimension of the left ventricle and a decrease in the ejection fraction suggestive of dilated cardiomyopathy were found in 12 carriers (75.0%). Tl-201 myocardial SPECT scan was performed in 2 symptomatic carriers and showed an area of hypoperfusion in the inferio-posterior wall. These findings were similar to previously reported findings in DMD patients. A biopsy of the myocardium was obtained in one carrier with her informed consent for the biopsy. Immunohistochemical staining demonstrated that 75.4% of the myocardial fibers were negative for dystrophin, suggesting that her cardiac dysfunction is caused by the abnormal expression of dystrophin in the cardiac muscle. On examination of the skeletal muscle function, none of the carriers had clinical evidence of muscle weakness or atrophy. However serum creatine kinase activity was elevated in 14 of 16 carriers (87.5%). Computed tomography (CT) of the lower limb muscles demonstrated widened spaces among muscles and moss-eaten appearance of low density areas within muscles and CT value was decreased, suggesting the subclinical involvement of the skeletal muscle. In the carriers without cardiac symptoms, there was a negative correlation (p < 0.05) between the end-diastolic dimension of the left ventricle and the CT value of the biceps femoris muscle (a muscle with the lowest CT value among the lower limb muscles). This indicates that there was an apparent correlation between the cardiac and skeletal muscle dysfunction. These findings suggest a high frequency of clinical and subclinical involvement of the cardiac and skeletal muscles in DMD carriers. To protect them from cardiac failure, cardiac dysfunction in DMD carriers needs to be examined closely and treated appropriately before the carriers become symptomatic.
Adult↗
ACE inhibition prevents myocardial infarction-induced skeletal muscle mitochondrial dysfunction.
Heart failure is associated with alterations in cardiac and skeletal muscle energy metabolism resulting in a generalized myopathy. We investigated the molecular and cellular effects of angiotensin-converting enzyme inhibition (ACEi) on skeletal muscle metabolism in infarcted animals. Myocardial infarction (MI) was obtained by left descending coronary artery ligation. Sham, MI, and MI-treated rats (perindopril, 2 mg.kg(-1).day(-1) given 7 days after MI) were studied 1 and 4 mo after surgery. Oxygen consumption of white gastrocnemius (Gas) muscle was studied in saponin-permeabilized fibers, using the main substrates of mitochondrial respiration. mRNA expression of nuclear factors (PGC-1alpha, NRF-2alpha, and mtTFA), involved in the transcription of mitochondrial proteins, and of MCIP1, a marker of calcineurin activation, were also determined. Echocardiographic left ventricular fractional shortening was reduced in both MI and perindopril group after 1 and 4 mo, whereas systemic blood pressure was reduced by 16% only in the MI group after 4 mo. The capacity of Gas to oxidize glutamate-malate, glycerol-triphosphate, or pyruvate (-30%, P < 0.01; -32%, P < 0.05; -33%, P < 0.01, respectively), was greatly decreased. Furthermore, PGC-1alpha (-54%), NRF-2alpha (-45%), and MCIP1 (-84%) gene expression were significantly downregulated. ACEi improved survival, left ventricular function, and blood pressure. Perindopril protected also totally the Gas mitochondrial function and preserved the mRNAs concentration of the mitochondrial transcriptional factors. Moreover, PGC-1alpha correlated with Gas oxidative capacity (r = 0.48), mitochondrial cytochrome-c oxidase (r = 0.65), citrate synthase (r = 0.45) activities, and MCIP1 expression (r = 0.44). Thus ACEi totally prevented MI-induced alterations of skeletal muscle mitochondrial function and protein expression, halting the development of this metabolic myopathy.
Angiotensin-Converting Enzyme Inhibitors↗
Mast cell chymase-like protease(s) modulates Escherichia coli lipopolysaccharide-induced vasomotor dysfunction in skeletal muscle in vivo.
This study investigated whether short-term exposure to Escherichia coli lipopolysaccharide (LPS) elicits vasomotor dysfunction in skeletal muscle in vivo and, if so, whether perivascular mast cell proteases partly modulate this response. With intravital microscopy, we found that suffusion of E. coli LPS on the in situ hamster spinotrapezius muscle for 60 min elicits immediate vasoconstriction followed by vasodilation. Vasoconstriction is abrogated by SK&F 108566, a selective, nonpeptide angiotensin II (AT II) subtype 1 receptor antagonist, chymostatin and soybean trypsin inhibitor. These compounds also attenuate E. coli LPS-induced vasodilation. By contrast, superoxide dismutase, catalase and indomethacin attenuate only E. coli LPS-induced vasodilation. Endothelin receptor antagonists, lisinopril, leupeptin, Bestatin and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid are ineffective. Histochemical analysis of the spinotrapezius muscle reveals abundant perivascular mast cells with chymostatin-inhibitable chymase-like activity. Pretreatment of hamsters with compound 48/80 for 4 days curtails E. coli LPS-induced vasoconstriction and converts vasodilation to vasoconstriction. On balance, these data indicate that E. coli LPS stimulates perivascular mast cells in the in situ hamster spinotrapezius muscle to release an AT II-producing chymase-like protease(s). AT II thus produced elicits local vasoconstriction and elaborates reactive oxygen species which, in turn, generate vasodilator prostaglandins.
Angiotensin II↗
Endotoxin-induced skeletal muscle contractile dysfunction: contribution of nitric oxide synthases.
The aims of this study were to assess the role of nitric oxide (NO) and the contribution of different NO synthase (NOS) isoforms in skeletal muscle contractile dysfunction in septic shock. Four groups of conscious rats were examined. Group 1 served as control; group 2, 3, and 4 were injected with Escherichia coli endotoxin [lipopolysaccharide (LPS), 20 mg/kg i.p.] and killed after 6, 12, and 24 h, respectively. Protein expression was assessed by immunoblotting and immunostaining. LPS injection elicited a transient expression of the inducible NOS isoform, which peaked 12 h after LPS injection and disappeared within 24 h. This expression coincided with a significant increase in nitrotyrosine formation (peroxynitrite foot-print). Muscle expression of the endothelial and neuronal NOS isoforms, by comparison, rose significantly and remained higher than control levels 24 h after LPS injection. In vitro measurement of muscle contractility 24 h after LPS injection showed that incubation with NOS inhibitor (S-methyliosothiourea) restored the decline in submaximal force generation, whereas maximal muscle force remained unaffected. We conclude that NO plays a significant role in muscle contractile dysfunction in septic animals and that increased NO production is due to induction of the inducible NOS isoform and upregulation of constitutive NOS isoforms.
Animals↗
Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance.
Insulin resistance in skeletal muscle is a characteristic feature of diabetes mellitus type 2 (DM2). Several lines of circumstantial evidence suggest that reduced mitochondrial oxidative phosphorylation capacity in skeletal muscle is a primary defect causing insulin resistance and subsequent development of DM2. We have now experimentally tested this hypothesis by characterizing glucose homeostasis in tissue-specific knockout mice with progressive respiratory chain dysfunction selectively in skeletal muscle. Surprisingly, these knockout mice are not diabetic and have an increased peripheral glucose disposal when subjected to a glucose tolerance test. Studies of isolated skeletal muscle from knockout animals show an increased basal glucose uptake and a normal increase of glucose uptake in response to insulin. In summary, our findings indicate that mitochondrial dysfunction in skeletal muscle is not a primary etiological event in DM2.
AMP-Activated Protein Kinases↗
High-intensity strength training in nonagenarians. Effects on skeletal muscle.
Muscle dysfunction and associated mobility impairment, common among the frail elderly, increase the risk of falls, fractures, and functional dependency. We sought to characterize the muscle weakness of the very old and its reversibility through strength training. Ten frail, institutionalized volunteers aged 90 +/- 1 years undertook 8 weeks of high-intensity resistance training. Initially, quadriceps strength was correlated negatively with walking time (r = -.745). Fat-free mass (r = .732) and regional muscle mass (r = .752) were correlated positively with muscle strength. Strength gains averaged 174% +/- 31% (mean +/- SEM) in the 9 subjects who completed training. Midthigh muscle area increased 9.0% +/- 4.5%. Mean tandem gait speed improved 48% after training. We conclude that high-resistance weight training leads to significant gains in muscle strength, size, and functional mobility among frail residents of nursing homes up to 96 years of age.
Aged↗
ROS in the local and systemic pathogenesis of COPD.
An imbalance between oxidants and antioxidants is proposed in the pathogenesis of COPD. Potential alterations responsible for an imbalance in oxidant production and intra- and extracellular antioxidant defense systems are discussed with respect to COPD-related changes in the pulmonary compartment. In line with the current view of COPD as a disease with multiple systemic consequences, there is increasing evidence that imbalances in the redox milieu extend beyond the diseased lung in COPD patients. Skeletal muscle dysfunction is often observed in COPD and may result from imbalances in the redox environment of skeletal muscle. Potential triggers of oxidative stress in the muscle compartment include inflammation and hypoxia, and local sources of reactive oxygen and nitrogen species are discussed, as well the mechanisms by which skeletal muscle trophical state, contractility and fatigability may be affected by oxidative stress, resulting in skeletal muscle dysfunction.
Animals↗
Chronic corticosteroid administration causes mitochondrial dysfunction in skeletal muscle.
Corticosteroid myopathy is a major clinical problem in patients undergoing chronic corticosteroid treatment and shows insidious and progressive muscle atrophy in proximal limbs. Although several mechanisms underlying the pathophysiology of muscle injury have been postulated, precise pathogenesis is still not clear. We evaluated the mitochondrial functions in patients receiving corticosteroids compared with those in healthy controls or patients not receiving corticosteroids. The serum levels and total production of lactate were investigated by an aerobic exercise test using a bicycle ergometer. Mitochondrial respiratory activities and oxidative damage in biopsied skeletal muscles were also studied. The results of aerobic exercise tests revealed a significant overproduction of lactate in patients treated with corticosteroids ( p < 0.005), which was positively correlated with total corticosteroid doses administered ( p < 0.0001). In these patients, mitochondrial enzyme activity in complex I was significantly decreased ( p < 0.05) and oxidative damage of biopsied skeletal muscle was remarkable both in mitochondrial and nuclear DNAs ( p < 0.001). The results suggest that chronic corticosteroid administration induces mitochondrial dysfunction and oxidative damage in skeletal muscles, which may be the pathogenesis, at least in part, of corticosteroid-induced myopathy.
8-Hydroxy-2'-Deoxyguanosine↗
Exercise in chronic pulmonary disease: resistance exercise prescription.
Resistance exercise training has received relatively little attention as a means to reduce the muscle dysfunction and ensuing exercise intolerance seen in chronic pulmonary diseases. To date, only a few studies have examined the characteristics of skeletal muscle function or its responsiveness to strength training in patients with chronic respiratory diseases. It is clear from these studies, however, that peripheral muscle, particularly muscles of ambulation, are weak in patients with lung disease, exhibiting effort-dependent strength scores that are 70--80% of these measures in age-matched healthy subjects. The degree to which this dysfunction is accounted for by deconditioning, disease-related myopathy, or other causes is unclear. It is evident, however, that patients with chronic respiratory diseases can acquire and maintain substantial improvements in skeletal muscle function, physical function, and quality of life through participation in a well-structured program of resistance exercise training. Despite the positive, albeit limited, evidence that skeletal muscle dysfunction may be improved with resistance training, no clear guidelines are available for this purpose. This review discusses the skeletal muscle dysfunction that accompanies chronic respiratory disease and presents strategies for resistance exercise training that may be considered as part of pulmonary rehabilitation. These strategies are derived from the successful outcomes noted in studies using resistance training in patients with COPD as well as on extrapolations from extant guidelines used to develop strength, power, and endurance in healthy individuals.
Exercise Therapy↗