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PubMed2005

Oxidative stress and respiratory muscle dysfunction in severe chronic obstructive pulmonary disease.

RATIONALE: Oxidative stress is involved in the skeletal muscle dysfunction observed in patients with severe chronic obstructive pulmonary disease (COPD). We hypothesized that the diaphragms of such patients might generate greater levels of oxidants than those neutralized by antioxidants. OBJECTIVES: To assess the levels of both oxidative and nitrosative stress and different antioxidants in the diaphragms of those patients, and to analyze potential relationships with lung and respiratory muscle dysfunctions. METHODS AND MEASUREMENTS: We conducted a case-control study in which reactive carbonyl groups, hydroxynonenal-protein adducts, antioxidant enzyme levels, nitric oxide synthases, and 3-nitrotyrosine formation were detected using immunoblotting and immunhistochemistry in diaphragm specimens (thoracotomy) obtained from six patients with severe COPD, six patients with moderate COPD, and seven control subjects. MAIN RESULTS: Diaphragms of patients with severe COPD showed both higher protein carbonyl groups and hydroxynonenal-protein adducts than control subjects. When only considering patients with COPD, negative correlations were found between carbonyl groups and airway obstruction, and between hydroxynonenal-protein adducts and respiratory muscle strength. Although diaphragmatic neuronal nitric oxide synthase did not differ among the three groups and no inducible nitric oxide synthase was detected in any muscle, muscle endothelial nitric oxide synthase was lower in patients with severe COPD than in control subjects. Muscle nitrotyrosine levels were similar in both patients with severe COPD and control subjects. CONCLUSIONS: This study shows that oxidative stress rather than nitric oxide is likely to be involved in the respiratory muscle dysfunction in severe COPD.

Aged↗

PubMed1983

Effects of parathyroid hormone on skeletal muscle protein and amino acid metabolism in the rat.

Because prominent skeletal muscle dysfunction and muscle wasting are seen in both chronic uremia and in primary hyperparathyroidism, and because markedly elevated parathyroid hormone levels occur in both disorders, potential effects of parathyroid hormone on skeletal muscle protein, amino acid, and cyclic nucleotide metabolism were studied in vitro using isolated intact rat epitrochlearis skeletal muscle preparations. Intact bovine parathyroid hormone and the synthetic 1-34 fragment of this hormone stimulated the release of alanine and glutamine from muscle of control but not from chronically uremic animals. This stimulation was dependent upon the concentration of parathyroid hormone added: At 10(5) ng/ml parathyroid hormone increased alanine release 84% and glutamine release 75%. Intracellular levels of alanine and glutamine were not altered by parathyroid hormone. Increasing concentrations of the 1-34 polypeptide decreased [(3)H]leucine incorporation into protein of muscles from both control and uremic animals. Using muscles from animals given a pulse-chase label of [guanido-(14)C]arginine in vivo, parathyroid hormone increased the rate of loss of (14)C label from acid-precipitable protein during incubation and correspondingly increased the rate of appearance of this label in the incubation media. Parathyroid hormone increased muscle cAMP levels by 140% and cGMP levels by 185%, but had no effect on skeletal muscle cyclic nucleotide phosphodiesterase activities as assayed in vitro. Adenylyl cyclase activity in membrane preparations from control but not uremic rats was stimulated by parathyroid hormone in a concentration-dependent fashion. However, no stimulation of guanylyl cyclase activity was noted by parathyroid hormone, although stimulation by sodium azide was present. Incubation of muscles with added parathyroid hormone produced a diminished responsiveness towards epinephrine or serotonin regulation of amino acid release and cAMP formation in the presence compared to the absence of parathyroid hormone. In the absence of parathyroid hormone, detectable inhibition of alanine and glutamine release was produced by 10(-9) M epinephrine, whereas in the presence of parathyroid hormone (1,000 ng/ml) inhibition of alanine and glutamine release required 10(-6) M or greater epinephrine. Resistance to cyclic AMP action as well as inhibition of cyclic AMP formation by parathyroid hormone was found. Preincubation of rat sarcolemma with 1-34 parathyroid hormone produced a decreased activity of the isoproterenol-stimulable adenylyl cyclase activity but there was no apparent change in the concentration of isoproterenol required for one-half maximal and maximal stimulation of the enzyme. These findings suggest that high levels of parathyroid hormone have direct effects on skeletal muscle protein, amino acid, and cyclic nucleotide metabolism in muscle of normal but not uremic animals. Treatment with these high levels of parathyroid hormone in vitro appears to reproduce in normal muscle, the metabolic deficits and loss of hormone responsiveness observed in muscle of chronically uremic animals. It is therefore possible that direct effects of parathyroid hormone on skeletal muscle may account in part for the muscle dysfunction and wasting of primary hyperparathyroidism and chronic uremia.

Adenylyl Cyclases↗

PubMed2026

Exerkine dysregulation links visceral adiposity to skeletal muscle impairment in end-stage heart failure with reduced ejection fraction: proteomic evidence for a cardio-adipose-muscle axis.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is associated with profound alterations in body composition, skeletal muscle dysfunction, and impaired exercise capacity. Exerkines representing exercise-responsive signaling molecules released by skeletal muscle, adipose tissue, and other organs may mediate systemic metabolic communication between tissues. However, their role in advanced HFrEF and their relationship with adiposity and skeletal muscle characteristics remain poorly understood. METHODS: We studied 73 patients with end-stage HFrEF and 16 healthy controls. Body composition was assessed using computed tomography, including visceral (VAT), subcutaneous (SAT), and epicardial adipose tissue (EAT), as well as skeletal muscle quantity (psoas muscle index, PMI) and quality (psoas muscle density, PMD). Functional performance was evaluated using handgrip strength (HGT) and the 6-min walk test (6MWT). Circulating exerkines were quantified using the Olink technology. Associations between proteins and clinical variables were assessed using age- and creatinine-adjusted linear models with false discovery rate correction. RESULTS: Among patients with HFrEF, 36% were obese and 38% exhibited central obesity independent of BMI. Muscle strength and muscle quality were strongly associated with functional capacity. VAT correlated with muscle mass but not with muscle quality or performance. Compared with controls, HFrEF patients demonstrated elevated inflammatory and metabolic stress-related exerkines including CXCL8, CCL2, IL-6, TNF, IL-15, GDF15, FGF21, ANGPTL4, CTSB, DCN, and resistin. In contrast, proteins associated with muscle integrity and regenerative signaling (myostatin, BDNF, IL-7, SPARC) were significantly reduced. In HFrEF patients leptin strongly correlated with adiposity measures. Metabolic stress mediators (GDF15, IL-15, FGF21, CTSB) were inversely associated with muscle quality and functional performance, whereas myostatin positively correlated with muscle quality, strength, and exercise capacity. BDNF was inversely associated with frailty. CONCLUSIONS: Advanced HFrEF is characterized by a dysregulated exerkine network linking adiposity, skeletal muscle quality, and functional performance. Four biologically coherent axes were identified: a leptin-driven adiposity axis, a metabolic stress-muscle quality axis, a myostatin-related muscle function axis, and a neurotrophic frailty axis. These findings support the presence of a systemic cardio-adipose-muscle signaling network in end-stage HFrEF and identify candidate molecular mediators of sarcopenia and functional decline.

Humans↗

PubMed2005

Skeletal muscle contractility is preserved in COPD patients with normal fat-free mass.

AIM: Peripheral muscle dysfunction often occurs in patients with chronic obstructive pulmonary disease (COPD). The muscle dysfunction may be caused by a loss of force-generating capacity, resulting from a loss of muscle mass, as well as by other alterations in contractile properties of skeletal muscle. METHODS: The maximal isometric voluntary strength and fatigability were determined in hand-grip and quadriceps muscles from nine male COPD patients (FEV(1) 30-50% predicted) and control subjects matched for fat-free mass (FFM), physical activity level and age. Contractile properties and fatigability of the quadriceps muscle were also studied with electrically evoked isometric contractions. RESULTS: The maximal voluntary force (MVC) and fatigability of the handgrip muscle did not differ between the COPD patients and control subjects. Also the MVC of the quadriceps muscle and the rate of force rise, contraction time, force-frequency relationship and fatigability, as determined with electrically evoked contractions, were similar in patients with COPD and control subjects. CONCLUSION: Skeletal muscle strength, contractile properties and fatigability are preserved in patients with moderate COPD and a normal FFM and activity level. This suggests that skeletal muscle dysfunction does not take place during moderate COPD until cachexia and/or a decline in physical activity occur.

Adipose Tissue↗

PubMed2001

Is there a relationship between muscle fatigue resistance and cardiovascular responses to isometric exercise in mild chronic heart failure?

BACKGROUND: Exercise intolerance in chronic heart failure (CHF) may be due to altered fatigue resistance and muscle afferent input to the cardiovascular system from dysfunctional skeletal muscle. AIM: To determine whether calf muscle fatigue resistance was associated with the magnitude of a muscle afferent driven cardiovascular response to isometric exercise. METHODS AND RESULTS: Cardiovascular responses were recorded in eight stable CHF patients (ejection fraction 20-40%) and nine healthy, age-matched controls during voluntary and electrically evoked isometric plantar flexion and post-exercise circulatory occlusion. The force developed by the plantar flexors during a 2-min submaximal electrically evoked fatigue test was measured. There was no relationship between ischaemic muscle fatigue and cardiovascular changes during and after voluntary contraction in either group nor evoked contraction in the CHF group. In the control group, the change in diastolic blood pressure (DBP) at the end of evoked contraction was related to the severity of fatigue at 90 s and 120 s (FI=0.01DeltaDBP+0.3, r=0.81, P<0.05 and FI=0.02DeltaDBP+0.8, r=0.84, P<0.01, respectively). CONCLUSION: Muscle fatigue resistance did not relate to the magnitude of the cardiovascular stress generated by isometric exercise of the same muscle in these patients.

Blood Pressure↗

PubMed2000

Muscle and motor-skill dysfunction in a K+ channel-deficient mouse are not due to altered muscle excitability or fiber type but depend on the genetic background.

The voltage-gated K+ channel Kv3.1 is expressed in skeletal muscle and in GABAergic interneurons in the central nervous system. Hence, the absence of Kv3.1 K+ channels may lead to a phenotype of myogenic or neurogenic origin, or both. Kv3.1-deficient (Kv3.1-/-) 129/Sv mice display altered contractile properties of their skeletal muscles and show poor performance on a rotating rod. In contrast, Kv3.1-/- mice on the (129/Sv x C57BL/6)F1 background display normal muscle properties and perform like wild-type mice. The correlation of poor performance on the rotating rod with altered muscle properties supports the notion that the skeletal muscle dysfunction in Kv3.1-/- 129/Sv mice may be responsible for the impaired motor skills on the rotating rod. Surprisingly, we did not find major differences between wild-type and Kv3.1-/- 129/Sv skeletal muscles in either the resting or action potential, the delayed-rectifier potassium conductance (gK) or the distribution of fast and slow muscle fibers. These findings suggest that the Kv3.1 K+ channel may not play a major role in the intrinsic excitability of skeletal muscle fibers although its absence leads to slower contraction and relaxation and to smaller forces in muscles of 129/Sv Kv3.1-/- mice.

Action Potentials↗

PubMed1986

Importance of purine nucleotide cycle to energy production in skeletal muscle.

The purpose of this study was to determine the role of the purine nucleotide cycle in aerobic energy production. Rats received either saline or 5-amino-4-imidazolecarboxamide riboside (AICAriboside), a precursor to an inhibitor of adenylosuccinate lyase (AICAR). Muscle tension was quantified during gastrocnemius stimulation, and muscle metabolite content was measured to obtain an estimate of the activity of the enzymes of the cycle. AICAriboside prevented the increase in synthetase and lyase activities observed in control animals during moderate (aerobic) stimulation, and was accompanied by marked muscle dysfunction. Although glycolytic energy production was not impaired in the AICAriboside-treated animals (lactate production occurred), total energy production did not meet energy demand. These results suggest that disruption of the purine nucleotide cycle impairs aerobic energy metabolism. Tetanic (anaerobic) stimulation produced more rapid fatigue in the AICAriboside-treated group. Total energy production was again impaired in the AICAriboside-treated animals, but lactate production was similar in both groups. These findings suggest the loss of the initial aerobic component of energy generation in tetanically stimulated muscle of AICAriboside-treated animals. The results of this study indicate that disruption of the purine nucleotide cycle at the level of the synthetase and lyase reactions is associated with skeletal muscle dysfunction, and suggest that the cycle plays an anapleurotic role in providing citric acid cycle intermediates that enhance aerobic energy production in contracting skeletal muscle.

AMP Deaminase↗

PubMed2005

Differential contribution of clinical amounts of acetaldehyde to skeletal and cardiac muscle dysfunction in alcoholic myopathy.

Acute intoxication due to alcohol consumption has been known to elicit reversible skeletal and cardiac muscle dysfunction, or "alcoholic myopathy and cardiomyopathy". Sometimes, irreversible muscle damage can be induced after heavy alcohol drinking. Many researchers have proposed that acetaldehyde, the major oxidised product of alcohol, may be a primary factor underlying alcohol-induced muscle dysfunction. Because acetaldehyde is rapidly metabolised to acetate by aldehyde dehydrogenase (ALDH) mainly in the liver, blood concentration of acetaldehyde is maintained at a low level even after heavy alcohol intoxication. In alcoholics, blood acetaldehyde level is relatively high, probably due to hepatic inhibition of ALDH activity. Several mM of acetaldehyde have been used for studies of cardiac muscle contraction, the intracellular calcium transient, and the L-type calcium channel. In skeletal muscle, the calcium release channel/ryanodine receptor activity has been reported to be inhibited by exposure to 1 mM acetaldehyde. However, these observations were made using potentially lethal concentrations of acetaldehyde, so the hypothesis that acetaldehyde plays a crucial role on alcoholic myopathy is questionable. In this review, we will summarise the effect of alcohol and its major oxidised product, acetaldehyde, on skeletal and heart muscles and propose a toxic contribution of clinical concentrations of acetaldehyde to alcoholic myopathy. In addition, this review will include briefly the effect of acetaldehyde on diabetic cardiomyopathy.

Acetaldehyde↗

PubMed2004

Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation.

Huntington's disease (HD) is a neurodegenerative disorder with complex symptoms dominated by progressive motor dysfunction. Skeletal muscle atrophy is common in HD patients. Because the HD mutation is expressed in skeletal muscle as well as brain, we wondered whether the muscle changes arise from primary pathology. We used R6/2 transgenic mice for our studies. Unlike denervation atrophy, skeletal muscle atrophy in R6/2 mice occurs uniformly. Paradoxically however, skeletal muscles show age-dependent denervation-like abnormalities, including supersensitivity to acetylcholine, decreased sensitivity to mu-conotoxin, and anode-break action potentials. Morphological abnormalities of neuromuscular junctions are also present, particularly in older R6/2 mice. Severely affected R6/2 mice show a progressive increase in the number of motor endplates that fail to respond to nerve stimulation. Surprisingly, there was no constitutive sprouting of motor neurons in R6/2 muscles, even in severely atrophic muscles that showed other denervation-like characteristics. In fact, there was an age-dependent loss of regenerative capacity of motor neurons in R6/2 mice. Because muscle fibers appear to be released from the activity-dependent cues that regulate membrane properties and muscle size, and motor axons and nerve terminals become impaired in their capacity to release neurotransmitter and to respond to stimuli that normally evoke sprouting and adaptive reinnervation, we speculate that in these mice there is a progressive dissociation of trophic signalling between motor neurons and skeletal muscle. However, irrespective of the cause, the abnormalities at neuromuscular junctions we report here are likely to contribute to the pathological phenotype in R6/2 mice, particularly in late stages of the disease.

Acetylcholine↗

PubMed2003

Chronic obstructive pulmonary disease as a systemic disease: an epidemiological perspective.

Chronic obstructive pulmonary disease (COPD) has been increasingly recognised as a systemic disease. The hormonal, metabolic and musculoskeletal implications of the generalised processes involving oxidative stress, inflammatory mediators, cytokines, and endocrine hormones have only begun to be understood. Only a few studies have looked into the epidemiology of inflammatory markers in patients with chronic obstructive pulmonary disease. Common extrapulmonary effects of chronic obstructive pulmonary disease include skeletal muscle dysfunction, wasting and osteoporosis. The resulting effects of a systemic inflammation can be measured at specific extrapulmonary organs such as skeletal muscle or in more general terms using body composition, body weight or derived measures, and only a few studies have set the parameters in an epidemiological context. Nevertheless, these studies indicate an association between inflammatory markers and forced expiratory volume in one second not only in subjects with severe chronic obstructive pulmonary disease. Also, it is increasingly clear that systemic markers in chronic obstructive pulmonary disease have important effects on prognosis.

Biomarkers↗

PubMed2001

The effects of resistance exercise on skeletal muscle abnormalities in patients with advanced heart failure.

Resistance exercise increases muscular strength and endurance, which prevents injuries associated with musculoskeletal disorders, favorably alters muscle fiber type distribution, and up-regulates the genetic expression of certain enzymes seen in dysfunctional skeletal muscles. Although the benefits of resistance exercise are well documented in the literature, this form of exercise is not routinely recommended for patients with heart failure for fear of symptom exacerbation, and because of poor understanding of how best to prescribe this type of exercise. Because muscle atrophy and deconditioning states are common findings in patients with heart failure, these patients stand to benefit substantially from resistance training because this type of physical activity results in functional adaptations in the neuromuscular system. This article addresses changes in skeletal muscle pathophysiology that occur in patients with heart failure and the potential role resistance training may play in reversing this sequela, and recommends a weight lifting exercise prescription for these patients.

Aged↗

PubMed2005

Exercise training in chronic heart failure: correlation between reduced local inflammation and improved oxidative capacity in the skeletal muscle.

BACKGROUND: Chronic heart failure (CHF) is accompanied by an inflammatory activation which occurs both systemically and in the skeletal muscle. Exercise training has been shown to reduce the local expression of cytokines and inducible nitric oxide synthase (iNOS) in muscle biopsies of CHF patients. INOS-derived NO can inhibit oxidative phosphorylation and contribute to skeletal muscle dysfunction in CHF. DESIGN: To investigate the correlation between changes in local iNOS expression associated with regular exercise and changes in aerobic enzyme activities in the skeletal muscle of patients with CHF. Twenty male CHF patients [ejection fraction 25% (SE 2), age 54 (SE 2) years] were randomized to a training (n=10) or a control group (C, n=10). METHODS: At baseline and after 6 months skeletal muscle iNOS expression was measured by real-time polymerase chain reaction. INOS protein and protein nitrosylation were assessed by immunohistochemistry. Cytochrome c oxidase (COX) activity was quantified electrochemically using the Clark oxygen electrode. RESULTS: Exercise training led to a 27% increase in cytochrome c oxidase activity [from 21.8 (SE 3.2) to 27.7 (SE 3.5) nmol O2/mg per min, P=0.02 versus baseline]. Changes in iNOS expression and iNOS protein content were inversely correlated with changes in COX-activity (r=-0.60, P=0.01; r=-0.71, P<0.001). CONCLUSIONS: The inverse correlation between iNOS expression/iNOS protein content and COX-activity indicates that local anti-inflammatory effects may contribute to improved muscular oxidative metabolism.

Aged↗

PubMed1995

Dissociation between exertional symptoms and circulatory function in patients with heart failure.

BACKGROUND: Patients with heart failure frequently report exertional dyspnea and fatigue. These symptoms are usually attributed to circulatory dysfunction and therefore are typically treated with cardiovascular medications. Serial assessment of exertional symptoms has also become the principal method used to assess drug efficacy in heart failure. Nevertheless, the relation between exertional symptoms in heart failure and circulatory dysfunction remains uncertain. METHODS AND RESULTS: This study was undertaken to investigate the relation between exertional symptoms, ventilatory and skeletal muscle dysfunction, and circulatory function in patients with heart failure. To this end, 52 ambulatory patients with heart failure underwent hemodynamic monitoring during maximal treadmill exercise testing. During exercise, the severity of dyspnea and fatigue was evaluated on a scale of 6 to 20 (Borg scale). The level of perceived exercise intolerance during daily activities was evaluated with the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index. Maximal treadmill exercise increased the VO2 to 13.4 +/- 2.8 mL.min-1.kg-1, the dyspnea score to 15.7 +/- 2.3, the fatigue score to 14.8 +/- 3.4, the pulmonary wedge pressure to 28 +/- 11 mm Hg, and the pulmonary artery lactate concentration to 34.5 +/- 16.3 mg/dL and decreased the pulmonary artery hemoglobin oxygen saturation to 30 +/- 9%. The level of perceived dyspnea had no relation to the pulmonary wedge pressure and correlated only minimally with the level of excessive ventilation (r = 39). The level of perceived fatigue correlated only weakly with blood lactate concentration (r = .55). Eleven patients (21%) exhibited a normal cardiac output and wedge pressure < 20 mm Hg during exercise, 22 (42%) exhibited a normal cardiac output but wedge pressure > 20 mm Hg during exercise, and 19 (37%) exhibited reduced cardiac output and wedge pressure > 20 mm Hg during exercise. Despite these markedly different hemodynamic responses, all three groups exhibited similar levels of fatigue and dyspnea at comparable workloads and had comparable total scores for the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index. There was no relation between the Living With Heart Failure Questionnaire and peak exercise VO2 and only a weak correlation between the Dyspnea-Fatigue Index and peak VO2 (r = .48). CONCLUSIONS: The level of exercise intolerance perceived by patients with heart failure has little or no relation to objective measures of circulatory, ventilatory, or metabolic dysfunction during exercise. In patients who report severe exertional symptoms, it may be desirable to directly measure hemodynamic response to exercise to ensure that these symptoms are due to circulatory dysfunction.

Adult↗

PubMed2005

Aging and heart failure--similar syndromes of exercise intolerance? Implications for exercise-based interventions.

A classic hallmark of chronic heart failure (CHF) is exercise intolerance; however, the extent of exercise limitation is not correlated with the degree of left ventricular dysfunction. Over the past 2 decades it has become more and more evident that peripheral factors, such as skeletal muscle dysfunction, ventilatory abnormalities, and endothelial dysfunction, contribute the greater part to the limitation of exercise capacity. The molecular and pathophysiological changes observed in these organ systems are not always specific to the underlying CHF but rather represent a common pathway that is activated in several chronic disease processes, including severe chronic obstructive pulmonary disease, cancer, and in the normal aging process. A major contributing factor for skeletal muscle catabolism (i.e. elevated cytokine expression in the skeletal muscle) can be found in both normal healthy aging and in heart failure patients. It is reasonable to assume that the overlap of aging and CHF-associated changes in the skeletal muscle partially explains the disabling consequences of the CHF syndrome among elderly patients (nearly 80% of all patients hospitalized for CHF are >65 years old). Peripheral alterations in CHF are often not adequately treated in routine clinical care since standard pharmacological therapy is still focused on the cardiac function and neurohormonal alteration. Exercise training is a guideline-oriented adjuvant therapy with well-documented beneficial effects on exercise tolerance, skeletal muscle function, endothelial function, and respiration. In this review, the effects of exercise in aging and in CHF are compared and the parallel mechanisms are explored.

Aged↗

PubMed2005

Impairment of the activity of the xenobiotic-metabolizing enzymes arylamine N-acetyltransferases 1 and 2 (NAT1/NAT2) by peroxynitrite in mouse skeletal muscle cells.

Reactive nitrogen species and their by-products, such as peroxynitrite, modulate many physiological functions of skeletal muscle. Peroxynitrite generation occuring under specific conditions, such as inflammation, may also lead to skeletal muscle dysfunction and pathologies. Arylamine N-acetyltransferases (NATs) are xenobiotic-metabolizing enzymes (XMEs) involved in the detoxification and/or metabolic activation of several drugs and chemicals. In addition to other XMEs, such as gluthatione S-transferases or cytochromes P450, NAT enzymes are expressed in skeletal muscle. We show here that functional NAT1 and NAT2 isoforms are expressed in mouse myotubes and that peroxynitrite may impair their activity in these cells. We show that this inactivation is likely due to the irreversible modification of NATs catalytic cysteine residue in vivo. Our results suggest that peroxynitrite-dependent inactivation of muscle XMEs such as NATs may contribute to muscle dysfunction by impairing the biotransformation activity of this key cellular defense enzyme system.

Acetyl Coenzyme A↗

PubMed2005

Muscle carnitine in hypo- and hyperthyroidism.

Weakness is common in both hyper- and hypothyroidism, and skeletal muscle L-carnitine may play a role in this regard, as suggested by studies indicating abnormal levels of carnitine in serum and urine of patients with thyroid dysfunction. Skeletal muscle samples were obtained for carnitine analysis from control subjects, and from hyperthyroid and hypothyroid patients before and after treatment. There was a significant reduction in carnitine, especially the esterified portion, in hyperthyroid individuals, with a return to normal as euthyroid status was regained. In hypothyroid patients, there was a trend for carnitine to be lower than normal and for improvement once euthyroid status was attained. Our data indicate that muscle carnitine levels are affected by both hypo- and hyperthyroidism. A decrease in muscle carnitine in both conditions may contribute to thyroid myopathy.

Adult↗

PubMed2001

Combined cardiomyopathy and skeletal myopathy: a variant with atrial fibrillation and ventricular tachycardia.

This article describes a family characterized by combined cardiomyopathy and nonspecific skeletal myopathy who present in the third to fifth decades with cardiac manifestations but earlier have evidence of subtle skeletal muscle dysfunction. They differ from previously defined syndromes and potentially represent a different genetic expression or mutation. Cardiomyopathy presents with atrial arrhythmias including AF and atrial flutter. Life-threatening ventricular tachyarrhythmias occur next with onset of ventricular dysfunction. Electrophysiological study revealed sustained monomorphic VT. Affected family members benefitted from an ICD and progression to congestive heart failure (CHF) occurred late. Skeletal myopathy continues with marked progressive muscle weakness and inability to ambulate without assistance. Genetic analysis is currently ongoing. Neurological evaluation in all three family members revealed nonspecific myopathy affecting the psoas and iliopsoas muscles. Atrophy and wasting of the facial and temporalis muscles were common. Skeletal muscle biopsy revealed myofiber atrophy consistent with myopathy.

Atrial Fibrillation↗

PubMed1999

Impaired skeletal muscle performance in the early stage of cardiac pressure overload in rabbits: beneficial effects of angiotensin-converting enzyme inhibition.

Abnormalities of skeletal muscles are frequently observed in patients with congestive heart failure. In these patients, angiotensin-converting enzyme (ACE) inhibitors improve exercise performance. The present study was designed to assess whether skeletal muscle dysfunction develops in the early stage of cardiac overload and if so, whether such functional alterations can be prevented by ACE inhibition. Mechanical performance, cross-bridge (CB) properties, and myosin heavy chain composition were investigated in respiratory and limb skeletal muscles of rabbits with moderate cardiac hypertrophy, and after single therapy with the ACE inhibitor perindopril (PE). After constriction of the aorta, the rabbits were treated during a 10-week period with either PE (1 mg/kg/day; n = 9) or a placebo (PL; n = 15). A third group of sham-operated animals received PL (n = 10). Analyses were performed on isolated diaphragm and soleus strips. Compared with sham-operated animals (shams), peak tetanic tension in PL fell by 40% in diaphragm and 34% in soleus. There were no significant differences in peak tetanic tension and the maximum shortening velocity between PE and shams. In both muscles, the total number of CBs was significantly lower in PL than in shams, but did not differ between shams and PE. The elementary force per CB did not differ between groups. In both muscles, the myosin heavy chain composition did not differ between groups. The study demonstrated that intrinsic performance of diaphragm and soleus muscles was affected early in the development of chronic pressure overload. Single therapy with PE tended to preserve muscle strength, essentially by limiting the loss of CBs.

Angiotensin-Converting Enzyme Inhibitors↗