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PubMed1978

Myoglobin: methods and diagnostic uses.

Myoglobin is the oxygen-binding protein characteristic of skeletal and cardiac muscle. With muscle disease or dysfunction, myoglobin may enter the circulation, and after renal clearance, it may also appear in the urine. Therefore, the presence of myoglobinemia and myoglobinuria may serve as indicators of the presence and severity of muscle disease. With newly developed methods of detection, myoglobinemia and myoglobinuria are now recognized as complications of trauma, ischemia, surgery, states of exertion and stress, metabolic abnormalities, inherited enzyme disorders, toxin and drug actions, and inflammatory states. Infarction of the heart muscle also can be detected by myoglobin assay. Persistent myoglobinuric states may be complicated by renal failure and electrolyte imbalance. The diagnosis of myoglobinemia and myoglobinuria can be now confirmed with the use of immunoassay techniques. Although not yet widely available, they offer the possibility of the specificity and sensitivity needed for clinical use.

Humans↗

PubMed1994

Autosomal recessive neuromuscular disorder in a transgenic line of mice.

We have generated a line of transgenic mice that when homozygous for the transgene develop a severe, adult-onset neuromuscular disorder. This mutation is likely the result of the insertional inactivation of an endogenous gene by the transgene integration. The mutant mice have a gait abnormality with stiffened and/or splayed hind legs, and adopt a hunched posture with some exhibiting kyphosis of the thoracic spine. These symptoms progress gradually to severe motor dysfunction. Pathologic changes were found in skeletal muscle and peripheral nerve of the mutant animals. In young mice the muscles from both upper and lower extremities show necrosis and phagocytosis. In older mice, regeneration with muscle fiber splitting, internally located nuclei, and variable fiber size are conspicuous features. Interactions between Schwann cells and axons also appear disrupted in these animals. Although many peripheral axons are well myelinated, the nerve and nerve roots contain very large bundles of juxtaposed, bare axons, reminiscent of Schwann cell-axon interactions in early development. Within these bundles there are axons large enough to be myelinated. The relationship between the pathologic changes in the muscles and nerves is not clear. The phenotypic abnormalities of these animals resemble those that occur in the spontaneous mouse mutants dystrophia muscularis and myodystrophy. Nevertheless, the chromosomal position of the transgene integration site, which was mapped by fluorescent in situ hybridization to chromosome 11, indicates that this disorder represents a new neuromuscular mutation.

Animals↗

PubMed2004

Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective loss of motor neurons and progressive muscle wasting. Growing evidence indicates that mitochondrial dysfunction, not only occurring in motor neurons but also in skeletal muscle, may play a crucial role in the pathogenesis. In this regard, the life expectancy of the ALS G93A mouse line is extended by creatine, an intracellular energy shuttle that ameliorates muscle function. Moreover, a population of patients with sporadic ALS exhibits a generalized hypermetabolic state of as yet unknown origin. Altogether, these findings led us to explore whether alterations in energy homeostasis may contribute to the disease process. Here, we show important variations in a number of metabolic indicators in transgenic ALS mice, which in all shows a metabolic deficit. These alterations were accompanied early in the asymptomatic phase of the disease by reduced adipose tissue accumulation, increased energy expenditure, and concomitant skeletal muscle hypermetabolism. Compensating this energetic imbalance with a highly energetic diet extended mean survival by 20%. In conclusion, we suggest that hypermetabolism, mainly of muscular origin, may represent by itself an additional driven force involved in increasing motor neuron vulnerability.

Amino Acid Substitution↗

PubMed1995

Temporal correlation between maximum tetanic force and cell death in postischemic rat skeletal muscle.

To gain insight into the mechanisms responsible for muscle dysfunction after ischemia-reperfusion, a rat spinotrapezius muscle preparation was developed which enabled sequential measurements of in vivo maximum tetanic force production and cell death assessed using digital microfluorographic determination of propidium iodide (PI) staining. After 60 min of no-flow ischemia, maximum tetanic force fell significantly during 90 min of reperfusion compared with control, nonischemic muscles. The most striking fall was evident within 30 min of reperfusion and occurred concomitant with an explosive increase in PI-positive myocyte nuclei. Treatment with the oxygen radical scavenger, dimethylthiourea, attenuated both the fall in force and increased PI staining. Indeed, the rise in PI-positive nuclei correlated closely (r= 0.728) with the reduction of maximum tetanic force developed following ischemia and reperfusion under all conditions. Superoxide dismutase also attenuated the rise in PI-positive nuclei. Assessment of mitochondrial inner membrane potential (deltapsi) using Rhodamine 123 fluorescence revealed that myocytes with the lowest initial mitochondrial membrane potential were subject to the greatest injury after 90 min of reperfusion (r= 0.828). These results support the hypothesis that myocyte injury, as visualized by PI-staining, reflects an impaired contractile function in fibers with a low oxidative potential which is likely mediated by oxygen radicals.

Animals↗

PubMed1985

Effect of parathyroid hormone on energy metabolism of skeletal muscle.

Clinical states with primary or secondary hyperparathyroidism are associated with muscle dysfunction, suggesting that parathyroid hormone (PTH) may affect muscle metabolism. The present study examined the effect of 1-84 PTH and its amino-terminal fragment (1-34 PTH) on energy production, transfer, and utilization by skeletal muscle. Rats weighing 150 to 200 g were injected intraperitoneally with 1-84 or 1-34 PTH, 200 U/day, for 4 days, and control animals received vehicle only. The effect of the simultaneous administration of a calcium channel blocker, verapamil, was examined also. The muscle content of inorganic phosphorus, creatine phosphate, and adenine nucleotides were significantly (P less than 0.01) lower in the PTH-treated rats than in control animals. The hormone significantly reduced mitochondrial oxygen consumption without altering ADP:0 ratio, indicating reduced phosphorylation. Both 1-84 and 1-34 PTH produced significant (P less than 0.01) reduction in the activities of mitochondrial and myofibrillar CPK, and mitochondrial MgATPase. 1-84 PTH reduced the activity of myofibrillar CaATPase as well. There was a significant (P less than 0.01) increment in muscle uptake of 45Ca in the 1-84 PTH-treated rats. Verapamil abolished all the effects of PTH. Our data demonstrate that both 1-84 and 1-34 PTH impair energy production, transfer, and utilization. These biochemical derangements may, at least in part, underlie the myopathy observed in conditions associated with excess PTH.

Adenosine Diphosphate↗

PubMed2003

Cardiopulmonary bypass reduces peripheral microvascular contractile function by inhibition of mitogen-activated protein kinase activity.

BACKGROUND: Mitogen-activated protein kinases (MAPK) have been implicated in pathophysiologic responses to cardiopulmonary bypass (CPB). MAPK are deactivated by phosphatases, such as MAPK phosphatase-1 (MKP-1). We hypothesized that MAPK mediate peripheral microvascular contractile dysfunction caused by CPB in humans. METHODS: Skeletal muscle was harvested before and after CPB. Protein levels of MKP-1 and activated extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 were measured. MKP-1 gene expression was measured. Peripheral microvessel responses to vasopressors were studied by videomicroscopy. Contractile function also was measured after MAPK inhibition with PD98059 (ERK1/2) and SB203580 (p38). ERK1/2, p38, and MKP-1 were localized by immunohistochemistry and in situ hybridization. RESULTS: ERK1/2 and p38 activity was decreased in peripheral tissue after CPB. MKP-1 was increased after CPB. Contractile responses of peripheral arterioles to phenylephrine and vasopressin were decreased after CPB. Microvessel reactivity also was reduced after treatment with PD98059 and SB203580. ERK1/2, p38, and MKP-1 localized to peripheral arterioles in tissue sections. CONCLUSIONS: CPB reduces ERK1/2 and p38 activity in peripheral tissue, potentially by MKP-1. Contractile responses of peripheral arterioles to phenylephrine and vasopressin are dependent on ERK1/2 and p38 and are decreased after CPB. These results suggest that alterations in MAPK pathways in part regulate peripheral microvascular dysfunction after CPB in humans.

Aged↗

PubMed1997

Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction.

The combination of abnormally low plasma cystine and glutamine levels, low natural killer (NK) cell activity, skeletal muscle wasting or muscle fatigue, and increased rates of urea production defines a complex of abnormalities that is tentatively called "low CG syndrome." These symptoms are found in patients with HIV infection, cancer, major injuries, sepsis, Crohn's disease, ulcerative colitis, chronic fatigue syndrome, and to some extent in overtrained athletes. The coincidence of these symptoms in diseases of different etiological origin suggests a causal relationship. The low NK cell activity in most cases is not life-threatening, but may be disastrous in HIV infection because it may compromise the initially stable balance between the immune system and virus, and trigger disease progression. This hypothesis is supported by the coincidence observed between the decrease of CD4+ T cells and a decrease in the plasma cystine level. In addition, recent studies revealed important clues about the role of cysteine and glutathione in the development of skeletal muscle wasting. Evidence suggests that 1) the cystine level is regulated primarily by the normal postabsorptive skeletal muscle protein catabolism, 2) the cystine level itself is a physiological regulator of nitrogen balance and body cell mass, 3) the cyst(e)ine-mediated regulatory circuit is compromised in various catabolic conditions, including old age, and 4) cysteine supplementation may be a useful therapy if combined with disease-specific treatments such as antiviral therapy in HIV infection.

Animals↗

PubMed2005

Sepsis induces diaphragm electron transport chain dysfunction and protein depletion.

RATIONALE: Sepsis significantly alters skeletal muscle mitochondrial function, but the mechanisms responsible for this abnormality are unknown. OBJECTIVES: We postulated that endotoxin elicits specific changes in electron transport chain proteins that produce derangements in mitochondrial function. To examine this issue, we compared the effects of endotoxin-induced sepsis on mitochondrial ATP (adenosine triphosphate) formation and electron transport chain protein composition. METHODS AND MEASUREMENTS: Diaphragm mitochondrial oxygen consumption and mitochondrial nicotinamide adenine dinucleotide, reduced form, oxidase assays were measured in control rats (n=13) and rats given endotoxin (8 mg/kg/d) for 12 (n=14), 24 (n=14), 36 (n=14), and 48 h (n=13). Electron transport chain subunits from Complexes I, III, IV, and V were isolated using Blue Native polyacrylamide gel electrophoresis techniques. MAIN RESULTS: Endotoxin administration: 1) elicited large reductions in mitochondrial oxygen consumption (e.g., 201+/-3.9 SE natoms O/min/mg for controls and 101+/-4.5 SE natoms O/minutes/mg after 48 h endotoxin, p<0.001), in nicotinamide adenine dinucleotide, reduced form, oxidase activity (p<0.002), and in uncoupled respiration (p<0.001) and 2) induced selective reductions in two subunits of Complex I, three subunits of Complex III, one subunit of Complex IV, and one subunit of Complex V. The time course of depletion of protein subunits mirrored alterations in oxygen consumption. CONCLUSIONS: Our data indicate that endotoxin selectively depletes critical components of the electron transport chain that diminishes electron flow, reduces proton pumping and decreases ATP formation.

Adenosine Triphosphate↗

PubMed1987

Excessive intracellular zinc accumulation in cardiac and skeletal muscles of dystrophic hamsters.

Zinc has been reported to be important in protein synthesis, collagen crosslinking, membrane structure and function, cellular necrosis, muscle glycolysis, and cardiac dysfunction. As all these processes are affected by muscular dystrophy, we studied the Zn concentrations in the cardiac and skeletal muscles of 7-month-old male dystrophic hamsters with advanced hypertrophic cardiomyopathy. Age- and sex-matched normal hamsters served as controls. Calcium, magnesium, and copper concentrations were also measured in the dystrophic and normal tissues. Flame atomic absorption spectrophotometry was used for mineral quantitation of the nitric acid tissue extracts. Zn concentrations in the myocardium (P less than 0.002), diaphragm (P less than 0.005), and rectus femoris muscles (P less than 0.001) were significantly elevated with concomitant elevations of Ca in dystrophic compared with normal hamsters. Although no appreciable changes in Cu or Mg concentrations were noted in the myocardium, slight depletions of Cu in the dystrophic diaphragm (P less than 0.025) and Mg in the dystrophic rectus femoris (P less than 0.05) were present. The intracellular Zn and Ca accumulations in the cardiac and skeletal muscles of dystrophic hamsters correlated with other dystrophic features such as increased rates of protein synthesis, significant myocardial enlargement, characteristic electrocardiographic and mechanophysiologic abnormalities, and classical histopathologic changes. We hypothesize that Zn2+ may be cotransported with Ca2+ across the cellular membrane or substituted for Ca2+ in certain pathways. These mechanisms may be affected by the high-energy ATP-pump and/or the sodium-potassium exchange system at the cellular level. Our observations suggest a possible pathogenetic involvement of Zn in muscular dystrophy which may be associated with an accelerated effort by the cellular system to repair the damaged cardiac and skeletal muscles.

Animals↗

PubMed2003

Cumulative effects of aging and mechanical ventilation on in vitro diaphragm function.

STUDY OBJECTIVE: Unloading the diaphragm, via mechanical ventilation (MV), results in significant diaphragmatic atrophy, contractile dysfunction, and oxidative stress in young adult animals. Since aging increases skeletal muscle susceptibility to atrophy and injury, we tested the hypothesis that MV-induced diaphragmatic contractile dysfunction would be exacerbated in aging rats. METHODS: Fisher 344/Brown Norway hybrid rats (4 months old [young] and 30 months old [old]) were assigned to either control or MV groups. MV rats were anesthetized, tracheostomized, and ventilated with 21% O(2) for 12 h. Arterial BP, pH, and blood gas homeostasis were maintained in the MV animals throughout the experimental period. Animals in the control group were acutely anesthetized, and the diaphragms were immediately removed. Muscle strips from the mid-costal diaphragm were removed from each experimental animal, and contractile properties were studied in vitro. RESULTS: Compared to young control animals, aging (old control animals) was associated with a 13% decrease in maximal isometric tension (24.5 N/cm(2) vs 21.3 N/cm(2)). Although, MV induced similar relative losses (24%) in diaphragmatic isometric tension in both young and old animals receiving MV, the combined effects of aging and MV resulted in a 34% decrement in diaphragmatic isometric tension compared to young control animals (24.5 N/cm(2) vs 16.1 N/cm(2)). CONCLUSIONS: These data do not support the hypothesis that aging exacerbates the relative MV-induced impairment in diaphragmatic isometric tension. Nonetheless, the additive effects of aging and MV have dramatic effects on diaphragmatic force reserve. This could exacerbate weaning difficulties in older individuals receiving MV.

Aging↗

PubMed2000

Phosphorus 31 nuclear magnetic resonance spectroscopy suggests a mitochondrial defect in claudicating skeletal muscle.

OBJECTIVE: Decreased oxygen supply is generally accepted as the primary cause of muscle dysfunction in patients with peripheral arterial occlusive disease (PAOD) and intermittent claudication, although reported morphologic changes in the mitochondria of claudicating muscle suggest that impaired energy utilization may also play a role. With the measurement of the phosphate-rich compounds of muscle energy metabolism (adenosinetriphosphate [ATP], adenosinediphosphate [ADP], and phosphocreatine [PCr]) and pH, phosphorus P 31 magnetic resonance spectroscopy ((31)P MRS) provides a unique, noninvasive method to investigate this hypothesis further. METHODS: Calf muscle bioenergetics were studied in 12 men with moderate claudication (ankle-brachial index >/=0.5 and </=0.8) and 14 normal control subjects with the use of (31)P MRS and standard treadmill testing. Phosphorus MRS evaluation of the superficial posterior calf muscles was carried out with a 90-second submaximal isometric plantar flexion exercise. This mild exercise was chosen to permit in-magnet testing and to allow study of intrinsic mitochondrial efficiency under conditions of unchallenged blood flow. Phosphocreatine and ADP recovery time constants (t.c.), two very sensitive measures of oxidative mitochondrial function, as well as intracellular pH and ATP production via anaerobic glycolysis were determined during three exercise sessions and the results averaged and compared to known values obtained from a control population. RESULTS: During the (31)P MRS protocol, the end exercise intracellular pH (7.11 +/- 0.01 vs 7.11 +/- 0.01) and ATP production by anaerobic glycolysis (0.13 +/- 0.05 vs 0.14 +/- 0.03 mmol/L per second) were no different in PAOD patients versus control subjects, confirming that the protocol exercise did not significantly reduce oxygen supply. Phosphocreatine and ADP recovery t.c. (137 +/- 41 vs 44 +/- 3 seconds and 60 +/- 10 vs 29 +/- 2 seconds, respectively) were significantly slower than normal (P <.05, t test). There was, however, no correlation between these measures of mitochondrial function and any treadmill parameter (P >.5, Pearson moment correlation). CONCLUSIONS: Phosphorus 31 MRS provides the first direct evidence of defective energy metabolism in the mitochondria of claudicating calf muscle. This defect appears to be independent of both arterial flow and the severity of occlusive disease in patients with mild to moderate claudication. Coupled with documented ultrastructural and DNA abnormalities in the mitochondria of claudicating skeletal muscle, these data provide evidence for a secondary cause of muscle dysfunction in intermittent claudication.

Adenosine Diphosphate↗

PubMed2003

Mitochondrial dysfunction in myofibrillar myopathy.

'Myofibrillar myopathy' defines a myopathic condition with focal myofibrillar destruction and accumulation of degraded myofibrillar elements. Despite the fact that a number of mutations in different genes as well as cytotoxic agents lead to the disease, abnormal accumulation of desmin is a typical, common feature. Pathological changes of mitochondrial morphology and function have been observed in animal models with intermediate filament pathology. Therefore, in the present study we tested for mitochondrial pathology in skeletal muscle of five patients with the pathohistological diagnosis of myofibrillar myopathy. Screening for large-scale mtDNA deletions and the frequent MERRF (myoclonic epilepsy; ragged red fibres) and MELAS (mitochondrial encephalomyopathy; lactic acidosis; stroke) point mutations was negative in all patients. Histologically, all muscle biopsies showed nonspecific abnormalities of the oxidative/mitochondrial enzyme stainings (histochemistry for reduced nicotinamide adenine dinucleotide, succinic dehydrogenase, cytochrome c oxidase), only one of them had ragged red fibres and a significant number of cytochrome c oxidase-negative fibres. Upon biochemical investigation, four of our patients showed pathologically low respiratory chain complex I activities. Only one of our patients had a pathologically low complex IV activity, while the measurements of the others were within low normal range. The single patient with pathological values for both complex I and IV was the one with the clear histological hallmarks (ragged red and cytochrome c oxidase-negative fibres) of mitochondrial pathology. She also was the only patient with clinical signs hinting at a mitochondrial disorder. Together with data from observations in desmin- and plectin-deficient mice, our results support the view that desmin intermediate filament pathology in these cases is closely linked to mitochondrial dysfunction in skeletal muscle.

Aged↗

PubMed2000

[Mutations of the dystrophin gene in dilated cardiomyopathy].

X-linked dilated cardiomyopathy(XLDCM) is caused by mutations of the dystrophin gene, which was originally cloned as the responsible gene for Duchenne muscular dystrophy and Becker muscular dystrophy. Mutations due to XLDCM are centered on 5' end of the gene, especially M-promoter and the adjacent region. However, other mutations are dispersed and cannot be characterized. Three mechanisms have been proposed by which the involvement of cardiac muscle is so severe in spite of the lack of skeletal muscle symptoms; 1) up-regulation of B- and P-dystrophin in merely skeletal muscle compensating for the defect of M-dystrophin, 2) dysfunction of some parts of dystrophin specifically essential to cardiac muscle, 3) different expression patterns of mutant mRNA between cardiac and skeletal muscle.

Cardiomyopathy, Dilated↗

PubMed2005

Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle.

OBJECTIVE: Although early administration of ascorbate has been shown to protect against the microvascular dysfunction in sepsis, it is not clear if a delayed introduction of ascorbate also yields beneficial effects. The main objective was to determine the therapeutic window for treatment of an animal model of sepsis with bolus injection of ascorbate. We also determined if sepsis per se affects urinary excretion of ascorbate. DESIGN: Prospective, controlled laboratory study. SETTING: Animal laboratory in a university-affiliated research institute. SUBJECTS: Male Sprague-Dawley rats, 300-400 g of body weight. INTERVENTIONS: Rats were made septic by cecal ligation and perforation (CLP) and volume resuscitated by continuous saline infusion. Ascorbate bolus (7.6 mg/100 g of body weight) or saline vehicle was injected intravenously at 1, 6, or 24 hrs after CLP. MEASUREMENTS AND MAIN RESULTS: At 24 hrs post-CLP, sepsis caused antidiuresis and decreased plasma ascorbate concentration, but it did not affect urinary excretion of ascorbate in rats that received only saline. Sepsis also caused maldistribution of capillary blood flow in skeletal muscle. This maldistribution of flow was prevented by ascorbate injected at 6 hrs post-CLP. At 48 hrs post-CLP, in addition to the flow maldistribution, sepsis caused systemic arterial hypotension and fever that were prevented by both immediate (1 hr post-CLP) and delayed injections of ascorbate (24 hrs post-CLP). CONCLUSION: Despite volume resuscitation, the present model of sepsis resulted in maldistribution of capillary blood flow within 24 hrs and hypotension within 48 hrs. Our finding that intravenous bolus of ascorbate can protect against these deficits even if delayed 6-24 hrs after the septic insult shows, for the first time, that ascorbate can reverse microcirculatory dysfunction after the onset of sepsis.

Analysis of Variance↗

PubMed1999

Heart involvement in muscular dystrophies due to sarcoglycan gene mutations.

Mutations in the sarcoglycan genes cause autosomal-recessive muscular dystrophies. Because sarcoglycan genes and their protein products are highly expressed both in skeletal and cardiac muscle, patients with these mutations might be expected to be at risk to develop dilated cardiomyopathy. We therefore studied 13 patients with alpha-, beta-, gamma-sarcoglycan gene mutations by thorough cardiological assessment. Electrocardiographic or echocardiographic abnormalities were observed in about 30% of cases showing a severe course of muscular dystrophy. No correlation was found between the presence of cardiac abnormalities and the type of mutation or sarcoglycan gene involved. The cardiac involvement was never severe, but it may be detected in early stages of the muscle disease. The absence of overt cardiac dysfunction may be due to lower sarcoglycan protein expression in cardiac than skeletal muscle or to less sarcolemmal instability at the myocardial level, possibly related to the different distribution of forces generated by contraction of the myocardium with respect to proximal limb-girdle muscles.

Adolescent↗

PubMed2006

Dietary treatment in adult-onset type II glycogenosis.

Eight patients with adult-onset type II glycogenosis (GSD II), all carrying the IVS1-13T<G mutation, were treated with high-protein isocaloric diet for 3 years. We evaluated the usefulness of this approach through the assessment of the skeletal muscles (by manual muscle testing, quantitative isokinetic exercise, and muscle MRI) and the respiratory function (by spirometry). Three patients with mild or moderate disease severity refused the diet and were still monitored for comparison: they showed clinical (2 patients) or clinicoradiological (1 patient) progression of muscle weakness, while respiratory function remained unchanged. Among the patients accepting the dietary treatment, muscle strength remained unchanged, as did the degree of fatty infiltration and atrophy as assessed by muscle MRI; respiratory function worsened in 2/5 patients with severe baseline respiratory dysfunction. High-protein diet may stabilize disease progression at the skeletal muscles, but does not produce significant clinical improvements; moreover, the usefulness of this approach in patients with severe respiratory disease seems questionable.

Adult↗

PubMed2005

Exercise-induced serum enzyme elevations confounding the evaluation of investigational drug toxicity. Report of two cases in a vaccine trial.

Two subjects developed marked elevations in creatine kinase and other serum enzymes associated with mild myalgia during a randomized, double-blind, controlled Phase 1 clinical trial of an investigational live, attenuated vaccine against West Nile virus (ChimeriVax-WN02). One subject had received ChimeriVax-WN02 while the other subject was enrolled in an active control group and received licensed yellow fever 17D vaccine (YF-VAX). Subsequently, the clinical trial was interrupted, and an investigation was begun to evaluate the enzyme abnormalities. As daily serum samples were collected for determination of quantitative viremia, it was possible to define the enzyme elevations with precision and to relate these elevations to physical activity of the subjects, symptoms, and virological and serological measurements. Evaluation of both subjects clearly showed that skeletal muscle injury, and not cardiac or hepatic dysfunction, was responsible for the biochemical abnormalities. This investigation also implicated strenuous exercise as the cause of the apparent muscle injury rather than the study vaccines. As a result of this experience, subjects engaged in future early-stage trials of these live, attenuated viral vaccines will be advised not to engage in contact sports or new or enhanced exercise regimens for which they are not trained or conditioned. The inclusion of placebo control arm (in lieu of or addition to an active vaccine control) will also be useful in differentiating causally related serum enzyme elevations.

Adult↗

PubMed2001

[Value of training-induced effects on arterial vascular system and skeletal muscles in therapy of NYHA II/III heart failure].

Dynamic muscular exercise performed by healthy subjects leads to a rise in the left ventricular blood ejection with an acute increase in the local wall shear stress on the endothelium of the arterial vessels. These hemodynamic changes results in a release of endothelium-dependent relaxing factors, one of them concerns nitric oxide (NO). Therefore an arterial vasodilatation with an acute increase in the blood flow volume to the exercising muscle groups occurs. If more than 1/6 of the skeletal musculature is involved in exercise and if training duration exceeds 3-5 hours a week the chronically increased blood flow volume in the cardiovascular system triggers structural and functional changes of the heart and the arterial vessels. It develops a functional intact excentric hypertrophy of the myocardium; within the arterial vessels an increase in the diameter of the muscular arteries supplying the trained muscle groups occurs. These training-induced adaptations of the cardiovascular system are adjusted to improve the aerobic skeletal muscle metabolism. In congestive heart failure a pathological excentric myocardial hypertrophy is found. In this case the systolic myocardial function is impaired and the left ventricular ejection fraction is reduced already in early stages, so that the cardiac output can not be sufficiently increased during exercise. In addition a dysfunction of the endothelium of the arterial vessels occurs. As a consequence the endothelium-dependent arterial vasodilation is reduced, so that the peripheral arteries could not supply the muscle groups involved in exercise with enough blood flow volume. Therefore, the acute delivery of the working musculature with oxygen and energy substrates is insufficient, so that premature muscular fatigue occurs. The reduced exercise resistance of the patients leads chronically to a generalized skeletal muscle atrophy. Ultrastructural analysis revealed a decrease of oxidative type 1 muscle fibers with a relative increase of more glycolytic type 2 fibers. In addition, the volume density and the surface area of the cristae of mitochondria are reduced. All these changes results in a decrease of aerobic skeletal muscle metabolism independent of the blood flow volume, so that the physical fitness of the patients progressively decline. On the basis of the training-induced physiological adaptations of the cardiovascular system, a special exercise therapy supervised by a physician was developed for patients with congestive heart failure NYHA II/III. It have been shown that various exercise programs, which are adjusted to the degree of cardiac function impairment are suitable to restore the endothelial dysfunction of the arterial vessels as well as to cure the disturbed skeletal muscle metabolism in these patients independent of an improvement of cardiac function. Therefore in patients with congestive heart failure NYHA II/III who underwent regularly such an exercise therapy, the secondary impaired physical fitness could be rebuild without an excessive risk for an acute exercise-induced cardiovascular emergency.

Cardiac Output↗