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Exercise training alters skeletal muscle mitochondrial morphometry in heart failure patients

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Abstract

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. To examine the effect of exercise training on skeletal muscle mitochondrial size in chronic heart failure patients. 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. 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. 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.

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... Also (cryo)-electron microscopy (EM) analysis of fixed specimens has been widely applied to analyze mitochondrial (ultra )structure (e.g. [41,[166][167][168]). As a consequence, morphometric analyses have been historically important to quantify mitochondrial properties using EM images [169]. ...
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Mitochondria play a key role in signal transduction, redox homeostasis and cell survival, which extends far beyond their classical functioning in ATP production and energy metabolism. In living cells, mitochondrial content ("mitochondrial mass") depends on the cell-controlled balance between mitochondrial biogenesis and degradation. These processes are intricately linked to changes in net mitochondrial morphology and spatiotemporal positioning ("mitochondrial dynamics"), which are governed by mitochondrial fusion, fission and motility. It is becoming increasingly clear that mitochondrial mass and dynamics, as well as its ultrastructure and volume, are mechanistically linked to mitochondrial function and the cell. This means that proper quantification of mitochondrial morphology and content is of prime importance in understanding mitochondrial and cellular physiology in health and disease. This review first presents how cellular mitochondrial content is regulated at the level of mitochondrial biogenesis, degradation and dynamics. Next we discuss how mitochondrial dynamics and content can be analyzed with a special emphasis on quantitative live-cell microscopy strategies.
... Increase in mitochondrial volume density positively correlates with changes in VO 2 peak and anaerobic threshold exercise [112] or changes in type I fiber percentage, and negatively with muscle venous lactate for a given workload [113]. As exercise training in heart failure patients increases mitochondrial size [114], it is likely that it will also increase muscle oxidative capacity in skeletal muscle, resulting in increased exercise tolerance. In older human skeletal muscle, exercise enhances mitochondrial activity, which is likely related to the concomitant increase in mitochondrial biogenesis [115]. ...
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Twenty-four biopsy specimens from the lower leg muscles of 21 patients with intermittent claudication were studied by electron microscopy. Sixteen of the specimens contained hypertrophic, atrophic, autolytic, or phagocytic fibers, or other forms of macroscopic fiber degeneration. Of the pathological changes in the cell organelles, the most common was simple myofibrillar degeneration, followed by slightly pathological mitochondria and excessive accumulations of glycogen and lipofuscin. Different types of basement membrane alterations and central nuclei were present in 16 of the biopsy specimens. Most of the pathological changes were the same as those previously reported by others to occur in specific diseases of muscle. There was some positive correlation of the degree of pathological changes to the estimated clinical severity of claudication.
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We have examined muscle strength, mitochondrial enzyme activity, histochemistry and fibre size in the quadriceps muscle of 9 patients with severe chronic heart failure. A needle biopsy of the quadriceps muscle was taken with patients at rest. Maximum oxygen uptake was measured during treadmill exercise. Mean maximal oxygen consumption was 11.7 ml.kg-1.min-1. Isometric maximum voluntary contraction was reduced to 55% of the predicted value for weight. Eight biopsies were abnormal. Findings included increased acid phosphatase, increased interstitial cellularity, excess intracellular lipid accumulation, atrophy of both type I and II fibres and variation in size with hypertrophy and atrophy of fibers. Muscle fibre capillary density and the activity of mitochondrial enzymes were normal. Changes in skeletal muscle strength may play a role in the limitation of exercise capacity seen in patients with congestive heart failure.
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Muscle strength, muscle cross-sectional area, fiber size, fiber type distribution, capillarity, and mitochondrial volume were estimated before and after 6 weeks of heavy-resistance exercise. Isokinetic torque production of the knee extensor muscles increased by a total of 17.6%, mainly during the first half of the training period. The cross-sectional area of the vastus lateralis muscle increased by 8.4%, mainly during the second half of the training period. Morphometrically determined fiber size, fiber type distribution, and capillarity from biopsies of vastus lateralis did not change significantly with training. Likewise, the surface densities of inner and outer mitochondrial membranes as well as the volume density of myofibrils remained unchanged. In contrast, the volume density of mitochondria decreased by 9.6%. However, due to the increase in total muscle volume, the calculated absolute volume of mitochondria remained constant, whereas the absolute volume of myofibrils increased by 10%. It is concluded that strength training of short duration in previously untrained young male subjects does not change the ultrastructural composition of mitochondria and that the apparent dilution of mitochondria can quantitatively be accounted for by the increase in myofibrillar volume.
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Symptoms of congestive heart failure occur most commonly during exercise, but cardiac performance is usually quantitated at rest. The relation between exercise capacity and measurements of cardiac performance at rest is little known. Treadmill exercise was performed in 21 patients with heart failure due to cardiomyopathy. Exercise duration averaged 9.1 +/- 0.7 (standard error of the mean) minutes (normal value 12 or more minutes) and did not correlate with resting ejection fraction of 26.4 +/- 2.7 percent (r = -0.06). Left ventricular diastolic dimension of 6.6 +/0 0.2 cm, mean velocity of circumferential fiber shortening and ratio of preejection period to left ventricular ejection time did not correlate with treadmill time (r = -0.03). Repeat studies after treatment of heart failure also failed to show correlations between changes in exercise capacity and changes in left ventricular performance at rest. Thus, measures of left ventricular performance obtained at rest do not accurately reflect exercise tolerance and symptomatic status of patients with congestive heart failure.
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The present study was designed to evaluate the effect of an ambulatory training program on ultrastructural morphology and the oxidative capacity of skeletal muscle and its relation to central and peripheral hemodynamic variables in patients with chronic heart failure. Clinical evidence supports the hypothesis that exercise intolerance in patients with chronic heart failure is not only a consequence of low cardiac output, but is also a result of alterations in oxidative metabolism of skeletal muscle. Twenty-two patients were prospectively randomized either to a training group (mean [+/-SD] ejection fraction 26 +/- 9%, n = 12) participating in an ambulatory training program or to a physically inactive control group (ejection fraction 27 +/- 10%, n = 10). At baseline and after 6 months, patients underwent symptom-limited bicycle exercise testing, and central and peripheral hemodynamic variables were measured. Percutaneous needle biopsy samples of the vastus lateralis muscle were obtained at baseline and after 6 months. The ultrastructure of skeletal muscle was analyzed by ultrastructural morphometry. After 6 months, patients in the training group achieved an increase in oxygen uptake at the ventilatory threshold of 23% (from 0.86 +/- 0.2 to 1.07 +/- 0.2 liters/min, p < 0.01 vs. control group) and at peak exercise of 31% (from 1.49 +/- 0.4 to 1.95 +/- 0.4 liters/min, p < 0.01 vs. control group). There was no significant change in oxygen uptake at the ventilatory threshold and at peak exercise in the control group. The total volume density of mitochondria and volume density of cytochrome c oxidase-positive mitochondria increased significantly by 19% (from 4.7 +/- 1.5 to 5.6 +/- 1.5 vol%, p < 0.05 vs. control group) and by 41% (from 2.2 +/- 1.0 to 3.1 +/- 1.0 vol%, p < 0.05 vs. control group) after 6 months of regular physical exercise. Cardiac output at rest and at submaximal exercise remained unchanged but increased during maximal symptom-limited exercise from 11.9 +/- 4.0 to 14.1 +/- 3.3 liters/min in the training group (p < 0.05 vs. baseline; p = NS vs. control group). Peak leg oxygen consumption increased significantly by 45% (from 510 +/- 172 to 740 +/- 254 ml/min, p < 0.01 vs. control group). Changes in cytochrome c oxidase-positive mitochondria were significantly related to changes in oxygen uptake at the ventilatory threshold (r = 0.82, p < 0.0001) and at peak exercise (r = 0.87, p < 0.0001). Regular physical training increases maximal exercise tolerance and delays anaerobic metabolism during submaximal exercise in patients with stable chronic heart failure. Improved functional capacity is closely linked to an exercise-induced increase in the oxidative capacity of skeletal muscle.