Skeletal muscle response to short endurance training in heart transplant recipients

Objectives. We sought to examine the effects of endurance training on the ultrastructural characteristics of skeletal muscle in heart transplant recipients (HTRs) and age-matched control subjects (C).Background. Deconditioning is one of the factors involved in the peripheral limitation of exercise capacity of HTRs, and training has proven to be beneficial.Methods. Biopsies of the vastus lateralis muscle, analyzed by ultrastructural morphometry, and quadriceps muscle cross-sectional area, assessed by computed tomography (CT), were performed in 12 HTRs and 7 age-matched C before and 6 weeks after an endurance training program. Maximal oxygen uptake (peak V̇O₂) was determined by an incremental exercise test. Additionally muscle biopsies were performed before and after a 6-week control period in four HTRs to check for spontaneous improvement.Results. Training resulted in similar increases in peak V̇O₂(11% in HTRs, 8.5% in C), ventilatory threshold (23% in HTRs, 32% in C) and total endurance work (54% in HTRs, 31% in C). Volume density of total mitochondria increased significantly (26% in HTRs, 33% in C) with a predominant increase of subsarcolemmal mitochondrial volume density (74% in HTRs, 70% in C). The capillary/fiber ratio increased by 19% in C only. In the nontrained group, none of the structural markers was spontaneously modified.Conclusions. Six weeks of endurance training in HTRs and C led to similar improvements of aerobic work capacity. However, the decreased muscular capillary network in HTRs remained unchanged with training. Immunosuppressive therapy might be responsible for the discrepancy between the normal mitochondrial content and the reduced capillary supply of these patients.     

Physical activity is the key determinant of skeletal muscle mitochondrial function in type 2 diabetes

Context: Conflicting data exist on mitochondrial function and physical activity in type 2 diabetes mellitus (T2DM) development. Objective: The aim was to assess mitochondrial function at different stages during T2DM development in combination with physical exercise in longstanding T2DM patients. Design and Methods: We performed cross-sectional analysis of skeletal muscle from 12 prediabetic 11 longstanding T2DM male subjects and 12 male controls matched by age and body mass index. Intervention: One-year intrasubject controlled supervised exercise training intervention was done in longstanding T2DM patients. Main Outcome Measurements: Extensive ex vivo analyses of mitochondrial quality, quantity, and function were collected and combined with global gene expression analysis and in vivo ATP production capacity after 1 yr of training. Results: Mitochondrial density, complex I activity, and the expression of Krebs cycle and oxidative phosphorylation system-related genes were lower in longstanding T2DM subjects but not in prediabetic subjects compared with controls. This indicated a reduced capacity to generate ATP in longstanding T2DM patients only. Gene expression analysis in prediabetic subjects suggested a switch from carbohydrate toward lipid as an energy source. One year of exercise training raised in vivo skeletal muscle ATP production capacity by 21 ± 2% with an increased trend in mitochondrial density and complex I activity. In addition, expression levels of β-oxidation, Krebs cycle, and oxidative phosphorylation system-related genes were higher after exercise training. Conclusions: Mitochondrial dysfunction is apparent only in inactive longstanding T2DM patients, which suggests that mitochondrial function and insulin resistance do not depend on each other. Prolonged exercise training can, at least partly, reverse the mitochondrial impairments associated with the longstanding diabetic state.     

Exercise and nutritional interventions for improving aging muscle health

Skeletal muscle mass declines with age (i.e., sarcopenia) resulting in muscle weakness and functional limitations. Sarcopenia has been associated with physiological changes in muscle morphology, protein and hormonal kinetics, insulin resistance, inflammation, and oxidative stress. The purpose of this review is to highlight how exercise and nutritional intervention strategies may benefit aging muscle. It is well known that resistance exercise training increases muscle strength and size and evidence also suggests that resistance training can increase mitochondrial content and decrease oxidative stress in older adults. Recent findings suggest that fast-velocity resistance exercise may be an effective intervention for older adults to enhance muscle power and functional capacity. Aerobic exercise training may also benefit aging skeletal muscle by enhancing mitochondrial bioenergetics, improving insulin sensitivity, and/or decreasing oxidative stress. In addition to exercise, creatine monohydrate, milk-based proteins, and essential fatty acids all have biological effects which could enhance some of the physiological adaptations from exercise training in older adults. Additional research is needed to determine whether skeletal muscle adaptations to increased activity in older adults are further enhanced with effective nutritional interventions and whether this is due to enhanced muscle protein synthesis, improved mitochondrial function, and/or a reduced inflammatory response.     

Endurance training does not affect diaphragm mitochondrial respiration

We sought to determine if chronic endurance training would increase mitochondrial respiration or protein content in rat diaphragm muscle. To this end, 20 male Wistar rats were randomly assigned to control (C) or an 8-week endurance training (T) group, n = 10 per group. At the end of T, VO2 max was 13% greater in T (83.3 vs 73.8 ml X kg-1 X min-1) and peak max power output was 32% greater (2.63 vs 1.98 kg X m X min-1). Mitochondrial specific activities of pyruvate-malate and cytochrome oxidase (expressed per mg mitochondrial protein) in both plantaris and diaphragm were similar in C and T rats, as were ADP/O and respiratory control ratios. When expressed per gram wet weight, whole muscle homogenate oxygen uptake (pyruvate + malate) and cytochrome oxidase activity increased 36 and 23%, respectively (P less than 0.05) in plantaris from T rats but did not change in diaphragm. Control oxidative capacity and mitochondrial protein content in the diaphragm were ca. 2-fold those in control plantaris. Plantaris mitochondrial protein content increased ca. 50% with T while the diaphragm was unaffected. We conclude that: plantaris muscle oxidative capacity adapts to training by increasing mitochondrial protein content, since there was no evidence for functional improvement of existing mitochondria, and in the face of a substantial training effect in whole animal and plantaris, the T stimulus was not sufficient to induce mitochondrial protein changes in the diaphragm. This finding is the result of either a 'pre-adaptation' secondary to the diaphragm's high chronic activity, or a sub-threshold increase in diaphragm recruitment during the exercise conditions studied.     

Cardiac and skeletal muscle energy metabolism in heart failure: beneficial effects of voluntary activity

OBJECTIVE: Mitochondrial function and metabolic profile of slow and fast skeletal muscles and cardiac muscle are altered in chronic heart failure (CHF), suggesting a generalized metabolic myopathy in this disease. The aim of this study was to investigate the potential beneficial effects of voluntary activity on cardiac and skeletal muscle energetics in heart failure. METHODS: Heart failure was induced in rats by aortic stenosis. Four months after surgery, part of sham and CHF animals were randomly assigned to activity cages equipped with running wheels for 8 weeks or kept sedentary. Mitochondrial capacity and regulation were measured using saponin skinned fibers in left ventricle, slow and fast skeletal muscles, and metabolic and myosin profiles were established. RESULTS: Despite four times lower performances of CHF rats, alterations in metabolic and myosin parameters (oxidative capacity, mitochondrial enzymes, cytosolic and mitochondrial creatine kinase, myosin heavy chains) observed in all muscles of CHF animals were almost fully restored in soleus muscle though unchanged in heart and fast skeletal muscles. CONCLUSIONS: These results show the powerful beneficial effect of physical activity specifically on active slow oxidative skeletal muscle in CHF, without the worsening of cardiac muscle metabolism.     

Effects of exercise on mitochondrial content and function in aging human skeletal muscle

Skeletal muscle mitochondria are implicated with age-related loss of function and insulin resistance. We examined the effects of exercise on skeletal muscle mitochondria in older (age = 67.3 +/- 0.6 years) men (n = 5) and women (n = 3). Similar increases in (p <.01) cardiolipin (88.2 +/- 9.0 to 130.6 +/- 7.5 microg/mU creatine kinase activity [CK]) and the total mitochondrial DNA (1264 +/- 170 to 1895 +/- 273 copies per diploid of nuclear genome) reflected increased mitochondria content. Succinate oxidase activity, complexes 2-4 of the electron transport chain (ETC), increased from 0.13 +/- 0.02 to 0.20 +/- 0.02 U/mU CK (p <.01). This improvement was more pronounced (p <.05) in subsarcolemmal (127 +/- 48%) compared to intermyofibrillar (56 +/- 12%) mitochondria. NADH oxidase activity, representing total ETC activity, increased from 0.51 +/- 0.09 to 1.00 +/- 0.09 U/mU CK (p <.01). In conclusion, exercise enhances mitochondria ETC activity in older human skeletal muscle, particularly in subsarcolemmal mitochondria, which is likely related to the concomitant increases in mitochondrial biogenesis.     

American ginseng supplementation attenuates creatine kinase level induced by submaximal exercise in human beings

AIM: To investigate whether American ginseng (AG, Panax quinquefolium) supplementation was able to improve endurance exercise performance. METHODS: Thirteen physically active male college students were divided into two groups (AG or placebo) and received supplementation for 4 wk, before the exhaustive running exercise. Treadmill speed was increased to a pace equivalent to 80% VO_(2max) of the subject. A 4-wk washout period followed before the subjects crossed over and received the alternate supplement for the next 4 wk. They then completed a second exhaustive running exercise. The physiological variables that were examined included time to exhaustion and oxygen pulse. Moreover, the plasma creatine kinase (CK) and lactate were measured prior to the exercise, at 15 and 30 min during exercise, immediately after exercise, and 20, 40, 60, and 120 min after exercise. RESULTS: The major finding of this investigation was that the production plasma CK during the exercise significantly decreased for group AG than for group P. Secondary physiological finding was that 80% VO_(2max) running was not improved over a 4-wk AG supplementation regimen. CONCLUSION: Supplementation with AG for 4 wk prior to an exhaustive aerobic treadmill running reduced the leakage of CK during exercise, but did not enhance aerobic work capacity. The reduction of plasma CK may be due to the fact that AG is effective for the decrease of skeletal muscle cell membrane damage, induced by exercise during the high-intensity treadmill run.     

Training-induced improvement in lipid oxidation in type 2 diabetes mellitus is related to alterations in muscle mitochondrial activity. Effect of endurance training in type 2 diabetes

AIM: We investigated whether or not, in type 2 diabetic (T2D) patients, an individualized training effect on whole-body lipid oxidation would be associated with changes in muscle oxidative capacity. METHODS: Eleven T2D patients participated in the study. Whole-body lipid oxidation during exercise was assessed by indirect calorimetry during graded exercise. Blood samples for measuring blood glucose and free fatty acids during exercise, and muscle oxidative capacity measured from skeletal muscle biopsy (mitochondrial respiration and citrate synthase activity), were investigated in the patients before and after a 10-week individualized training program targeted at LIPOXmax, corresponding to the power at which the highest rate of lipids is oxidized (lipid oxidation at LIPOXmax). RESULTS: Training induced both a shift to a higher-power intensity of LIPOXmax (+9.1+/-4.2W; P<0.05) and an improvement of lipid oxidation at LIPOXmax (+51.27+/-17.93 mg min(-1); P<0.05). The improvement in lipid oxidation was correlated with training-induced improvement in mitochondrial respiration (r=0.78; P<0.01) and citrate synthase activity (r=0.63; P<0.05). CONCLUSION: This study shows that a moderate training protocol targeted at the LIPOXmax in T2D patients improves their ability to oxidize lipids during exercise, and that this improvement is associated with enhanced muscle oxidative capacity.     

Effects of selective and nonselective beta-adrenergic blockade on mechanisms of exercise conditioning

Exercise conditioning involves adaptations in the heart, peripheral circulation, and trained skeletal muscle that result in improved exercise capacity. Since the specific influence of beta-adrenergic stimulation on these various adaptations has not been clear, we studied the effect of beta 1-selective and nonselective beta-adrenergic blockade on the exercise conditioning response of 24 healthy, sedentary men after an intensive 6 week aerobic training program. Subjects randomly assigned to receive placebo, 50 mg bid atenolol, or 40 mg bid nadolol were tested before and after training both on and off drugs. Comparable reductions in maximal exercise heart rate occurred with atenolol and nadolol, indicating equivalent beta 1-adrenergic blockade. Vascular beta 2-adrenergic selectivity was maintained with atenolol as determined by calf plethysmography during intravenous infusion of epinephrine. All subjects trained at greater than 85% of maximal heart rate and 80% of VO2 max determined on drug. VO2 max increased after training 16 +/- 2% (p less than .05) in the placebo group and 6 +/- 2% (p less than .05) in the atenolol group, while there was no change in the nadolol group. At maximal exercise, subjects receiving placebo increased their exercise duration and oxygen pulse significantly greater than those receiving atenolol or nadolol. During submaximal exercise there were reductions in heart rate and heart rate-blood pressure product in all three groups, but these reductions were greater with placebo than with either drug. Leg blood flow during submaximal exercise decreased 24 +/- 2% (p less than .01) in the placebo group but was unchanged in the atenolol and nadolol groups. Lactates in arterialized blood during submaximal exercise were reduced equivalently in all three groups after training. Capillary/fiber ratio in vastus lateralis muscle biopsy specimens increased 31 +/- 6% in the placebo group and 21 +/- 6% in the atenolol group (both p less than .05) and tended to increase in the nadolol group. Succinic dehydrogenase and cytochrome oxidase activities in muscle biopsy specimens increased equivalently in all three groups, especially during submaximal exercise, these changes were less marked than that with placebo. While beta-adrenergic blockade attenuated the exercise conditioning response, skeletal muscle adaptations including increases in oxidative enzymes, capillary supply, and decreases in exercise blood lactates were unaffected. Cardiac and peripheral vascular adaptations do appear to be affected by beta-adrenergic blockade during training. Cardioselectivity does not seem to be important in modifying these effects.     

Skeletal muscle metabolism in overweight and post-overweight women: an isometric exercise study using (31)P magnetic resonance spectroscopy

OBJECTIVE: To investigate whether skeletal muscle anaerobic metabolism, oxidative metabolism or metabolic economy during controlled sub-maximal and near-maximal exercises is altered in overweight women after diet-induced weight reduction, and whether these parameters are different between normal-weight, obesity-prone and normal-weight obesity-resistant women with similar physical fitness levels. DESIGN: A prospective weight loss study of overweight women and their comparison with never overweight controls. SUBJECTS: Thirty overweight, nondiabetic, premenopausal women and 28 never overweight controls were included in this analysis. All were participating in a longitudinal investigation of the role of energy metabolism in the etiology of obesity.The overweight women were recruited specifically to have a positive family history of obesity and have a body mass index (BMI) between 27 and 30 kg/m(2) and were studied in the overweight state and after reduction to a normal weight. The never-overweight controls were recruited specifically to have no personal and family history of obesity and were group matched with the weight-reduced post-overweight subjects in terms of premenopausal status, age, BMI, race and sedentary lifestyle. MEASUREMENTS: All testing was performed following one month of weight maintenance and during the follicular phase of the menstrual cycle. Hydrostatic weighing was performed to measure body composition and a whole-body maximal oxygen uptake (VO(2max)) test was done to measure aerobic fitness. (31)P MRS was used to determine ATP production from oxidative phosphorylation (OxPhos), 'anaerobic' glycolysis (AnGly), and creatine kinase (CK), as well as muscle metabolic economy. The time constant of ADP (TC(ADP)), V(PCr) (ie the initial rate of PCr resynthesis following exercise), and Q(max) (ie the apparent maximal oxidative ATP production rate) were also calculated as additional markers of mitochondrial function. RESULTS: Diet-induced weight loss did not have any effects on the anaerobic metabolism markers (AnGly and CK). The aerobic metabolism markers calculated from the initial recovery data (OxPhos and V(PCr)) were unaffected by diet-induced weight loss. However, diet-induced weight loss resulted in improvements in the TC(ADP) and Q(max) in the post-overweight state as compared to their overweight state. There were no differences in any of the anaerobic (AnGly and CK) or oxidative metabolism markers (OxPhos, V(PCr), Q(max) and TC(ADP)) between the post-overweight and control groups. CONCLUSIONS: Once the overweight women were reduced to a normal-weight state, their skeletal muscle energy metabolism and economy was similar to the never overweight control women. In overweight women, oxidative metabolism or mitochondrial function may be limited by blood flow to the muscle following the cessation of exercise.     

Abnormalities in exercising skeletal muscle in congestive heart failure can be explained in terms of decreased mitochondrial ATP synthesis, reduced metabolic efficiency, and increased glycogenolysis.

OBJECTIVE: To distinguish between the effects of reduced oxidative capacity and reduced metabolic efficiency on skeletal muscle bioenergetics during exercise in patients with congestive heart failure. DESIGN AND PATIENTS: Patients were studied by 31P magnetic resonance spectroscopy during aerobic exercise and recovery, and results compared with controls. RESULTS: In flexor digitorum superficialis muscle (26 patients) there was a 30% decrease in oxidative capacity compared with control (mean (SE) 36 (2) v 51 (4) mM/min) and also a 40% decrease in "effective muscle mass" (5 (1) v 9 (1) arbitrary units), probably at least partly the result of reduced metabolic efficiency. Both contribute to increased phosphocreatine depletion and intracellular acidosis during exercise. However, an increased concentration of ADP (an important mitochondrial regulator) during exercise permitted near-normal rates of oxidative ATP synthesis. Results were similar in gastrocnemius muscle (20 patients), with a 30% decrease in maximum oxidative capacity (29 (4) v 39 (3) mM/min) and a 65% decrease in effective muscle mass (5 (1) v 13 (2) arbitrary units). Exercise training improved maximum oxidative capacity in both muscles, and in gastrocnemius effective muscle mass also. CONCLUSIONS: Skeletal muscle exercise abnormalities in patients with congestive heart failure results more from decreased metabolic efficiency than from the abnormalities in mitochondrial oxidation. Both decreased efficiency and defective mitochondrial oxidation result in an increased activation of glycogen phosphorylase, and may be improved by exercise training.     

Effect of Alcohol and Electrical Stimulation on Leakage of Creatine Kinase from Isolated Fast and Slow Muscles of Rat

Binge drinking of alcohol may lead to acute alcoholic myopathy with rhabdomyolysis, which is characterized by skeletal muscle damage, elevated serum creatine kinase (CK), and myoglobinuria. This study was undertaken to test whether alcohol acts directly on the skeletal muscles to enhance the leakage of CK, and to assess the influence of fiber-type composition and repetitive contractions of the muscle on the effect of alcohol. After 4 hr of incubation in normal physiological solution at 37°C, mean leakage of CK was 0.7 units/mg from isolated rat extensor digitorum longus (EDL), which has more fast-twitch glycolytic muscle fibers, and 1.2 units/mg from the soleus, which has more slow-twitch oxidative muscle fibers. Ethanol at 0.1, 0.2, and 0.5% concentrations caused significantly greater increase in leakage of CK from soleus than from EDL. In normal physiological solution, electrical stimulation at 1 Hz for 4 hr increased the leakage of CK by about the same degree in both EDL and soleus. In the presence of 0.1 and 0.2% ethanol, electrical stimulation markedly potentiated the alcohol-induced leakage of CK from both soleus and EDL. These results indicate that alcohol increases the leakage of CK by acting directly on skeletal muscle fibers, especially of the slow-twitch oxidative type, and that repeated muscle contractions potentiate the alcohol effect. These studies suggest that exercise may increase the chances of rhabdomyolysis in the alcoholics.     

Impaired Exercise Tolerance in Heart Failure: Role of Skeletal Muscle Morphology and Function

Purpose of Review

To discuss the impact of deleterious changes in skeletal muscle morphology and function on exercise intolerance in patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), as well as the utility of exercise training and the potential of novel treatment strategies to preserve or improve skeletal muscle morphology and function.

Recent Findings

Both HFrEF and HFpEF patients exhibit a reduction in percent of type I (oxidative) muscle fibers and oxidative enzymes coupled with abnormal mitochondrial respiration. These skeletal muscle abnormalities contribute to impaired oxidative metabolism with an earlier shift towards glycolytic metabolism during exercise that is strongly associated with exercise intolerance. In both HFrEF and HFpEF patients, peripheral “non-cardiac” factors are important determinants of the improvement in exercise tolerance following aerobic exercise training. Adjunctive strategies that include nutritional supplementation with amino acids and/or anabolic drugs to stimulate anabolic molecular pathways in skeletal muscle show great promise for improving exercise tolerance and treating heart failure-associated sarcopenia, but these efforts remain early in their evolution, with no immediate clinical applications.

Summary

There is consistent evidence that heart failure is associated with multiple skeletal muscle abnormalities which impair oxygen uptake and utilization and contribute greatly to exercise intolerance. Exercise training induces favorable adaptations in skeletal muscle morphology and function that contribute to improvements in exercise tolerance in patients with HFrEF. The contribution of skeletal muscle adaptations to improved exercise tolerance following exercise training in HFpEF remains unknown and warrants further investigation.

     

Decreased mitochondrial oxygen consumption and antioxidant enzyme activities in skeletal muscle of dystrophic mice after low-intensity exercise

To evaluate low-intensity exercise training induced changes of mitochondrial metabolism in dystrophic skeletal muscle, oxygen consumption, reactive oxygen species (ROS) scavengers and antioxidant enzymes were measured in control (C57BL/10) and dystrophic (mdx) mice at 10 (young) and 22 (adult) weeks of age. Dystrophic and control mice were either kept sedentary or daily exercised on a treadmill (480 m/day, exercise training was initiated at 4 and 16 weeks of age for 6 weeks' duration). Mitochondrial oxygen consumption was significantly lower in skeletal muscle from exercised young compared to sedentary young dystrophics. Whereas oxygen consumption was unchanged in exercised adult dystrophics, exercised adult controls exhibit a significant increase vs. sedentary adult controls. Contents of TBARS and lipofuscin were increased (+48%, +24%), while alpha-tocopherol concentration tended to decrease (p > 0.05) in exercised vs. sedentary young dystrophics. Compared to sedentary groups, glutathione peroxidase activity was decreased in exercised young dystrophic muscle (-12%), but increased in exercised controls (young controls +60%, adult controls +47%). In conclusion, adaptation to exercise-induced formation of ROS was limited in young dystrophic skeletal muscle but regained in that of adults.     

Exercise training alters skeletal muscle mitochondrial morphometry in heart failure patients

BACKGROUND: Previous research has demonstrated that exercise intolerance in heart failure patients is associated with significant alterations in skeletal muscle ultrastructure and oxidative metabolism that may be more consequential than cardiac output. DESIGN: To examine the effect of exercise training on skeletal muscle mitochondrial size in chronic heart failure patients. METHODS: Six heart failure patients participated in 16-weeks of supervised upper and lower extremity exercise training. At the conclusion of training, percutaneous needle biopsies of the vastus lateralis were taken and electron microscopy was used to assess mitochondrial sizes. RESULTS: The exercise programme resulted in a significant increase in peak maximal oxygen consumption ( P< 0.05) and anaerobic threshold (P < 0.04). Knee extension muscle force increased following training ( P< 0.02). After exercise training, the average size of the mitochondria increased by 23.4% (0.036 to 0.046 mu(2), P< 0.015) and the average shape was unaltered. CONCLUSION: Exercise training with heart failure patients alters skeletal muscle morphology by increasing mitochondrial size, with no change in shape. This may enhance oxidative metabolism resulting in an increased exercise tolerance.     

Exercise training increases adipose tissue GLUT4 expression in patients with type 2 diabetes

We investigated the effects of exercise training on adipose tissue and skeletal muscle GLUT4 expression in patients with type 2 diabetes (T2D). Muscle and adipose tissue samples were obtained before and after 4-weeks of exercise training in seven patients with T2D [47 ± 2 years, body mass index (BMI) 28 ± 2]. Seven control subjects (54 ± 4, BMI 30 ± 2) were recruited for baseline comparison. Adipose tissue GLUT4 protein expression was 43% lower (p < 0.05) in patients with T2D compared with control subjects and exercise training increased (p < 0.05) adipose tissue GLUT4 expression by 36%. Skeletal muscle GLUT4 protein expression was not different between control subjects and patients with T2D. Exercise training increased (p < 0.05) skeletal muscle GLUT4 protein expression by 20%. In conclusion, 4-weeks of exercise training increased GLUT4 expression in adipose tissue and skeletal muscle of patients with T2D, although the functional benefits of this adaptation appear to be dependent on an optimal β-cell function.     

Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance

OBJECTIVES: The purpose of the study was to investigate if apoptosis occurs in skeletal muscle myocytes and its relation to exercise intolerance in patients with chronic heart failure (CHF). BACKGROUND: Intrinsic abnormalities of skeletal muscle frequently limit exercise tolerance in CHF patients. Recently, apoptosis has been detected in cardiac myocytes of patients with CHF, suggesting that apoptosis may contribute to the reduced contractile force. The presence and regulation of apoptosis in skeletal myocytes of patients with CHF remains to be defined. METHODS: Skeletal muscle biopsies (m. vastus lateralis) of 34 CHF patients (New York Heart Association functional class II-III) and eight age-matched healthy control subjects were analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling for the presence of apoptosis, and by immunohistochemistry and videodensitometrical quantification for inducible nitric oxide synthase (iNOS) and Bcl-2 expression. Maximal oxygen consumption (VO2max) was determined by ergospirometry. RESULTS: Apoptosis was detected in 16/34 (47%) patients with CHF and in none of the healthy subjects. Patients with apoptosis-positive skeletal muscle myocytes exhibited a significantly lower VO2max (12.0 +/- 3.7 vs. 18.2 +/- 4.4 ml/kg/min; p = 0.0005), a higher iNOS expression (6.8 +/- 3.6 vs. 3.7 +/- 2.6% iNOS-positive stained tissue area; p = 0.015) and a lower Bcl-2 expression (1.0 +/- 0.3 vs. 1.4 +/- 0.4% Bcl-2-positive tissue area; p = 0.03) as compared with patients with apoptosis-negative biopsies. CONCLUSIONS: These results indicate that apoptosis is frequently found in skeletal muscle obtained from CHF patients, which is associated with significant impairment of functional work capacity. In skeletal muscle of these patients, iNOS and Bcl-2 are possibly involved in the regulation of apoptosis.     

Unexplained exertional limitation: characterization of patients with a mitochondrial myopathy

Exercise intolerance is a common complaint, the cause of which often remains elusive after a comprehensive evaluation. In this report, we describe 28 patients with unexplained dyspnea or exertional limitation secondary to biopsy-proven mitochondrial myopathies. Patients were prospectively identified from a multidisciplinary dyspnea clinic at a tertiary referral center. All patients were without underlying pulmonary, cardiac, or other neuromuscular disorders. Patients underwent history, physical examination, complete pulmonary function testing, respiratory muscle testing, cardiopulmonary exercise testing, and muscle biopsy. Results were compared with a group of normal control subjects. The estimated period prevalence was 8.5% (28 of 331). Spirometry, lung volumes, and gas exchange were normal in patients and control subjects. Compared with control subjects, the patient group demonstrated decreased exercise capacity (maximum achieved V O(2) 67 versus 104% predicted; p < 0.0001) and respiratory muscle weakness (PI(max) 77 versus 115% predicted; p = 0.001). These patients have a characteristic exercise response that was hyperventilatory (peak VE/V CO(2); 55 versus 42) and hypercirculatory (maximum heart rate - baseline heart rate/V O(2)max - baseline V O(2)max; 91 versus 41) compared to control subjects. Patients stopping exercise due to dyspnea (n = 16) (as compared with muscle fatigue, n = 11) displayed weaker respiratory muscles (Pdi(max) 61 versus 115 cm H(2)O; p = 0.01) and were more likely to reach mechanical ventilatory limitation (V Emax/ MVV 0.81 versus 0.58; p = 0.02). The sensation of dyspnea was related to indices of respiratory muscle function including respiratory rate and inspiratory flow. We conclude that mitochondrial myopathies are more prevalent than previously reported. The characteristic physiological profile may be useful in the diagnostic evaluation of mitochondrial myopathy.