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PubMed1992

Physical training in patients with congestive heart failure.

Multiple compensatory mechanisms operate to preserve exercise tolerance in patients with left ventricular failure. Exercise capacity of most patients with chronic heart failure is limited by dyspnea or fatigue, or both. Maximal stress testing with direct assessment of peak O2 uptake is an essential measurement in planning exercise conditioning programs, which are now attracting patients with chronic heart failure. The biochemical and histologic patterns of skeletal muscle changes seen in chronic heart failure patients are consistent with the effects of long-term exercise deconditioning in normal subjects. Recent studies have suggested beneficial effects of training in subjects with moderate or even severe left ventricular dysfunction by showing increased exercise tolerance or peak O2 consumption, anaerobic threshold, peak leg blood flow, peak central arteriovenous oxygen difference and decreased lactate accumulation. However, a number of questions remain unanswered. Exercise training for the treatment of chronic heart failure should be determined on an individual basis and used with caution.

Exercise↗
PubMed2005

Myocardial insulin resistance and cardiac complications of diabetes.

Cardiovascular disease is a major cause of mortality and morbidity in individuals with obesity, type 2 diabetes and the metabolic syndrome. The mechanisms for this are partially understood, but include increased atherosclerosis, hypercoagulability and increased hypertension. Epidemiological data suggests however, that a component of the excess cardiovascular mortality occurs independently of underlying coronary artery disease. Indeed, diabetes is an independent risk factor for the development of heart failure and the mechanisms responsible remain to be clarified. Insulin resistance in skeletal muscle, adipose tissue and the liver are widely recognized features of obesity and type 2 diabetes, and contribute to the pathogenesis of impaired glucose homeostasis. Insulin resistance has also been described in the vasculature, and may contribute to endothelial dysfunction and atherosclerosis. The heart is an insulin responsive organ and less is known about whether or not the heart becomes insulin resistant in diabetes and what the pathogenic consequences of this might be. This review will discuss the currently available evidence from human and animal studies, that the heart may become insulin resistant in obesity and type 2 diabetes. The potential consequences of this on cardiac structure, function and metabolism will be discussed as well as recent data from transgenic mice with perturbed cardiac insulin sensitivity that have shed interesting new insight into potential mechanisms linking cardiac insulin resistance with myocardial dysfunction in diabetes.

Animals↗
PubMed2006

Effect of lifelong overexpression of HSP70 in skeletal muscle on age-related oxidative stress and adaptation after nondamaging contractile activity.

Skeletal muscle aging is characterized by atrophy, a deficit in specific force generation, increased susceptibility to injury, and incomplete recovery after severe injury. The ability of muscles of old mice to produce heat shock proteins (HSPs) in response to stress is severely diminished. Studies in our laboratory using HSP70 overexpressor mice demonstrated that lifelong overexpression of HSP70 in skeletal muscle provided protection against damage and facilitated successful recovery after damage in muscles of old mice. The mechanisms by which HSP70 provides this protection are unclear. Aging is associated with the accumulation of oxidation products, and it has been proposed that this may play a major role in age-related muscle dysfunction. Muscles of old wild-type (WT) mice demonstrated increased lipid peroxidation, decreased glutathione content, increased catalase and superoxide dismutase (SOD) activities, and an inability to activate nuclear factor (NF)-kappaB after contractions in comparison with adult WT mice. In contrast, levels of lipid peroxidation, glutathione content, and the activities of catalase and SOD in muscles of old HSP70 overexpressor mice were similar to adult mice and these muscles also maintained the ability to activate NF-kappaB after contractions. These data provide an explanation for the preservation of muscle function in old HSP70 overexpressor mice.

Actins↗
PubMed2001

Intervention approaches against I/R-induced arterial insufficiency in reconstructive surgery.

Ischemia and reperfusion in skeletal muscle is unavoidable during many reconstructive surgeries. Typical examples include replantation, transplantation, and free muscle transfer. One important complication during or after surgery is arterial insufficiency or a no-reflow phenomenon. The microcirculation is a primary target of ischemia and reperfusion injury. Vasoconstriction, poor blood flow, and capillary no-reflow, are the prominent features in the microcirculation seen during reperfusion. Currently, extensive efforts have focused on the theory that reactive oxygen species induce endothelial dysfunction in the microcirculation during reperfusion. Some intervention approaches, including ischemic preconditioning, are developing to interfere with or modulate the pathophysiological processes that are set in motion during ischemia and reperfusion.

Arterial Occlusive Diseases↗
PubMed2005

Mitochondrial dysfunction and type 2 diabetes.

Insulin resistance plays a major role in the pathogenesis of the metabolic syndrome and type 2 diabetes, and yet the mechanisms responsible for it remain poorly understood. Magnetic resonance spectroscopy studies in humans suggest that a defect in insulin-stimulated glucose transport in skeletal muscle is the primary metabolic abnormality in insulin-resistant patients with type 2 diabetes. Fatty acids appear to cause this defect in glucose transport by inhibiting insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated phosphatidylinositol 3-kinase activity. A number of different metabolic abnormalities may increase intramyocellular and intrahepatic fatty acid metabolites; these include increased fat delivery to muscle and liver as a consequence of either excess energy intake or defects in adipocyte fat metabolism, and acquired or inherited defects in mitochondrial fatty acid oxidation. Understanding the molecular and biochemical defects responsible for insulin resistance is beginning to unveil novel therapeutic targets for the treatment of the metabolic syndrome and type 2 diabetes.

Diabetes Mellitus, Type 2↗
PubMed2005

Nesprin-2 is a multi-isomeric protein that binds lamin and emerin at the nuclear envelope and forms a subcellular network in skeletal muscle.

Nesprin-2 is a multi-isomeric, modular protein composed of variable numbers of spectrin-repeats linked to a C-terminal transmembrane domain and/or to N-terminal paired calponin homology (CH) domains. The smaller isoforms of nesprin-2 co-localize with and bind lamin A and emerin at the inner nuclear envelope (NE). In SW-13 cells, which lack lamin A/C, nesprin-2 epitopes and emerin were both mislocalized and formed aggregates in the endoplasmic reticulum (ER). The larger isoforms and other CH-domain-containing isoforms co-localize with heterochromatin within the nucleus and are also present at the outer NE and in multiple cytoplasmic compartments. Nesprin-2 isoforms relocalize during in vitro muscle differentiation of C2C12 myoblasts to the sarcomere of myotubes. Immunogold electron microscopy using antibodies specific for three different epitopes detected nesprin-2 isoforms at multiple locations including intranuclear foci, both membranes of the NE, mitochondria, sarcomeric structures and plasma membrane foci. In adult skeletal muscle, confocal immunolocalization studies demonstrated that nesprin-2 epitopes were present at the Z-line and were also associated with the sarcoplasmic reticulum (SR) in close apposition to SERCA2. These data suggest that nesprin-2 isoforms form a linking network between organelles and the actin cytoskeleton and thus may be important for maintaining sub-cellular spatial organisation. Moreover, its association at the NE with lamin and emerin, the genes mutated in Emery-Dreifuss muscular dystrophy, suggests a mechanism to explain how disruption of the NE leads to muscle dysfunction.

Actin Cytoskeleton↗
PubMed2004

Comparative analysis of parvalbumin and SERCA2a cardiac myocyte gene transfer in a large animal model of diastolic dysfunction.

Diastolic dysfunction results from impaired ventricular relaxation and is an important component of human heart failure. Genetic modification of intracellular calcium-handling proteins may hold promise to redress diastolic dysfunction; however, it is unclear whether other important aspects of myocyte function would be compromised by this approach. Accordingly, a large animal model of humanlike diastolic dysfunction was established through 1 yr of left ventricular (LV) pressure overload by descending thoracic aortic coarctation in canines. Serial echocardiography documented a progressive increase in LV mass. Diastolic dysfunction with preserved systolic function was evident at the whole organ and myocyte levels in this model, as determined by hemispheric sonomicrometric piezoelectric crystals, pressure transducer catheterization, and isolated myocyte studies. Gene transfer of the sarco(endo)plasmic reticulum calcium-ATPase (SERCA2a) and parvalbumin (Parv), a fast-twitch skeletal muscle Ca(2+) buffer, restored cardiac myocyte relaxation in a dose-dependent manner under baseline conditions. At high Parv concentrations, sarcomere shortening was depressed. In contrast, during beta-adrenergic stimulation, the expected enhancement of myocyte contraction (inotropy) was abrogated by SERCA2a but not by Parv. The mechanism of this effect is unknown, but it could relate to the uncoupling of SERCA2a/phospholamban in SERCA2a myocytes. Considering that inotropy is vital to overall cardiac performance, the divergent effects of SERCA2a and Parv reported here could impact potential therapeutic strategies for human heart failure.

Animals↗
PubMed2005

The mammalian exercise pressor reflex in health and disease.

The exercise pressor reflex (a peripheral neural reflex originating in skeletal muscle) contributes significantly to the regulation of the cardiovascular system during exercise. Exercise-induced signals that comprise the afferent arm of the reflex are generated by activation of mechanically (muscle mechanoreflex) and chemically sensitive (muscle metaboreflex) skeletal muscle receptors. Activation of these receptors and their associated afferent fibres reflexively adjusts sympathetic and parasympathetic nerve activity during exercise. In heart failure, the cardiovascular response to exercise is augmented. Owing to the peripheral skeletal myopathy that develops in heart failure (e.g. muscle atrophy, decreased peripheral blood flow, fibre-type transformation and reduced oxidative capacity), the exercise pressor reflex has been implicated as a possible mechanism by which the cardiovascular response to physical activity is exaggerated in this disease. Accumulating evidence supports this conclusion. This review therefore focuses on the role of the exercise pressor reflex in regulating the cardiovascular system during exercise in both health and disease. Updates on our current understanding of the exercise pressor reflex neural pathway as well as experimental models used to study this reflex are presented. In addition, special emphasis is placed on the changes in exercise pressor reflex activity that develop in heart failure, including the contributions of the muscle mechanoreflex and metaboreflex to this pressor reflex dysfunction.

Afferent Pathways↗
PubMed2002

Cardiovascular hemodynamics and exercise tolerance in thyroid disease.

The heart is an organ sensitive to the action of thyroid hormone, and measurable changes in cardiovascular performance are detected with small variations in thyroid hormone serum concentrations. Most patients with thyroid disease experience cardiovascular manifestations, and the most serious complications of thyroid dysfunction occur as a result of cardiac involvement. The increased metabolic state and oxygen consumption that occur in hyperthyroid patients require an increased supply of oxygen and removal of metabolic products from the periphery. This is accomplished by increasing the cardiac output to meet the needs of the periphery. Circulation time is decreased in hyperthyroid patients, and a lowered arterial resistance and increased venous resistance promote the return of blood to the heart. Thyroid hormones may significantly decrease the strength of respiratory and skeletal muscles and affect regulatory mechanisms of adaptation to incremental effort. In hyperthyroidism, cardiovascular exercise testing and analysis of respiratory gas exchange demonstrate low efficiency of cardiopulmonary function as well as impaired chronotropic, contractile, and vasodilatatory reserves, which are reversible when euthyroidism is restored. During exercise, the increment (delta) of minute ventilation (respiratory rate x tidal volume), and oxygen pulse (oxygen uptake per heart beat) are significantly lower in dysthyroidism versus euthyroidism. Especially in older patients with thyroid dysfunction, markedly reduced workload, delta ejection fraction, and delta heart rate, both at the anaerobic threshold as well as at maximal exercise, are observed. In thyrotoxicosis, mitochondria oxidative dysfunction during exercise mostly causes intracellular acidosis, whereas in hypothyroidism, inadequate cardiovascular support appears to be one of the principal factors involved. These abnormalities partly explain why subjects with dysthyroidism are intolerant to exertion. Thus, in thyroid disease, both cardiac structures and function may remain normal at rest, however impaired cardiovascular and respiratory adaptation to effort becomes unmasked during exercise.

Age Factors↗
PubMed2000

The effects of limb elevation and increased intramuscular pressure on nerve and muscle function in the human leg.

In this study we investigated the effects of increased intramuscular pressure (IMP) on nerve and muscle function in the leg and foot. In study A, muscle pressure was increased by inducing venous stasis in both legs, placed in plaster casts, of eight healthy subjects having a mean age of 29 years. The results from elevated and non-elevated limbs were compared. In study B, two different models for increasing IMP were studied in nine healthy subjects having a mean age of 32 years. The results of increased IMP and decreased blood perfusion pressure on local (= leg) and distal (= foot) function of muscle and nerve induced by venous stasis of a leg in a plaster cast and by external compression of the contralateral leg were compared. Contraction pressure of the tibialis anterior muscle in the leg was recorded. A biphasic compound muscle action potential was measured from the extensor hallucis brevis and the extensor digitorum muscles as an indication of foot muscle function. Muscle contraction pressure was 87 (SD 38) mm Hg in the vein-obstructed leg and 133 (SD 42) mm Hg in the externally compressed leg (P<0.05). In both studies the skin sensibility of the feet was significantly lower in the vein-obstructed elevated leg after 30 min (P<0.05). Vein stasis in an elevated human leg in a plaster cast defines a model for simulating imminent acute compartment syndrome with reversible neuromuscular dysfunction.

Action Potentials↗
PubMed2005

Immune activation is associated with reduced skeletal muscle mass and physical function in chronic heart failure.

BACKGROUND: Chronic heart failure is characterized by immune activation and increased circulating levels of cytokines. Whether humoral factors contribute to the peripheral manifestations of the heart failure syndrome, such as muscle atrophy and reduced physical work capacity, however, is not clear. METHODS: We measured circulating cytokines (tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6)), their soluble receptors (sTNF-alpha RII, IL-6sR), markers of immune activation (C-reactive protein (CRP)), muscle mass, aerobic capacity and muscle strength in 10 patients with heart failure (mean +/- S.E.; 63 +/- 3 years) and 11 controls (70 +/- 3 years). RESULTS: Heart failure patients exhibited decreased aerobic capacity (P < 0.01) and leg muscle strength (P < 0.05). Reduced muscle strength persisted in heart failure patients after statistical adjustment for differences in skeletal muscle size. All inflammatory markers were increased in heart failure patients (P < or = 0.05 to P < 0.01) compared to controls, with the exception of TNF-alpha. Despite no group differences in TNF-alpha, higher concentrations of this cytokine were correlated to lower skeletal muscle mass in the combined study population (range of r-values: -0.436 to -0.545; P < 0.05 to P < 0.02), as were IL-6 levels (range of r-values: -0.438 to -0.443; P < 0.05). TNF-alpha, sTNF-alpha RII, IL-6 and CRP showed strong negative relationships to aerobic capacity (range of r-values: -0.579 to -0.751; P < 0.01 to P < 0.001). In addition, elevated levels of IL-6 and TNF-alpha were associated with reduced leg and forearm skeletal muscle strength (range of r-values: -0.440 to -0.674; P < 0.05 to P < 0.01). Finally, correlations between cytokines and functional measures were present when heart failure patients were analyzed separately (range of r-values: -0.646 to -0.673; P < 0.05). CONCLUSIONS: Our results suggest that circulating cytokines are related to both skeletal muscle mass and physical function. These findings provide further evidence to support the hypothesis that immune activation contributes to skeletal muscle atrophy and reduced functional capacity in heart failure patients.

Aged↗
PubMed1999

The blood vessel, linchpin of diabetic lesions.

The morbidity and mortality associated with diabetes mellitus are essentially related to the vascular lesions that develop over time in this condition. Both the macrocirculation and microcirculation are involved, and as a consequence, vital organs such as the brain, retina, heart, and kidney and the limbs become damaged. Because microalbuminuria represents the earliest and probably most sensitive indication of endothelial dysfunction in diabetes mellitus, the results of pharmacologic intervention with angiotensin-converting enzyme inhibitors, which treat glomerular hypertension were the first indication of potential beneficial effects in reducing diabetic nephroplasty. The nature of endothelial dysfunction related to diabetes is probably not homogeneous, since microcirculation networks are affected at different periods and with variable intensity. This appears to be the case for the aorta, the heart, segments of the digestive tract, the skin, and the skeletal muscle, the largest consumer of insulin. Although the aorta and large arteries contain a small portion of the total blood volume, their distribution of blood flow (pulse pressure) to peripheral organs may affect endothelial function in the microcirculation. Changes in the structure of conduit arteries, partly responsible for the alteration in compliance characteristics, could well be related to the way these arteries are fed by the vasa vasorum system. This report describes a new in vitro approach to examine capillary permeability in normal and alloxan-induced diabetic rabbits. Preliminary results indicate that the size of terminal arterioles of the vasa vasorum (increased diameter) and the capillary permeability to albumin (markedly enhanced) in this specialized network are profoundly affected in the thoracic aorta obtained from diabetic animals. Albumin extravasation into the interstitial fluid compartment of the aorta is likely to lead to structural and physicochemical changes: in fact, removal of interstitial macromolecules via lymphatic drainage is poor in the blood vessel wall of large arteries. This experimental approach is likely to be useful in the exploration of medications affecting the structure and function of conduit vessels.

Animals↗
PubMed2002

Alarming atrioventricular block and mitral valve prolapse in the Kearns-Sayre syndrome.

Kearns-Sayre syndrome (KSS) is a multisystem mitochondrial disorder characterized by the invariant triad: onset before 20, progressive external ophthalmoplegia and pigmentary retinal degeneration, plus at least one of the following: complete (or not) heart block, cereberal dysfunction and CSF protein above 100 mg/dl. Autopsies from patients with KSS revealed widespread tissue distribution mtDNA deletions. These deletions result in significantly lower activities of the enzymes of the respiratory chain. The same deletion of mitochondrial DNA present in skeletal muscle is found in myocardial tissue. An 18-year-old girl diagnosed with the KSS was admitted to our hospital because of an upper respiratory tract infection and dysphagia. ECG showed cardiac conduction defects. The patient had no history of syncope. At her surface ECG there was a complete RBBB (QRS duration approximately 130 ms), a clockwise rotation with an axis of approximately 90 degrees and a slight QT prolongation (420 ms). Echocardiography showed prolapse with thickening and degeneration of both mitral valve leaflets but without mitral regurgitation. The patient was started on a diet rich in potassium and pharmaceutical therapy with magnesium oxide (240 mg of elemental Mg p.o. per day), 1 g of calcium carbonate t.i.d., vitamin D (calcitriol 0.25 microg p.o. per day) and coenzyme Q(10) 100 mg daily and discharged 6 days later with slightly improved biochemical profile but apparent clinical improvement. Urgent pacemaker implantation was decided but unfortunately the patient died due to acute cardiac arrest 10 days later.

Adolescent↗
PubMed1999

Three-dimensional kinematics of the forefoot, rearfoot, and leg without the function of tibialis posterior in comparison with normals during stance phase of walking.

BACKGROUND: Many studies have shown that lack of functional activity of tibialis posterior leads to changes in the longitudinal arch and affects the motion of the foot. A quantitative description of the affects on the motion of the foot in detail has not been reported. OBJECTIVE: To describe three-dimensional motion of the leg, rearfoot and forefoot with tibialis posterior dysfunction during stance phase of walking in comparison with normals. This study compared one case without the function of tibialis posterior with the ensemble average of 10 normals (five males, five females). METHODS: Subjects with 10, 12 mm retroreflective markers placed on their right leg, rearfoot and forefoot, performed five trials of walking at self-selected speed on a 10 m walkway. A four-camera three-dimensional motion analysis system and a synchronized force platform were used to record three-dimensional motions of the segments and force variables during stance phase of walking. RESULTS: The patterns and range of motion of the rearfoot relative to the leg, and the forefoot relative to the rearfoot demonstrated some differences between the tibialis posterior dysfunction case and normals. Most of the major differences occurred from just prior to heel-off through to toe-off, the period when a stable arch would be required. CONCLUSION: The observed differences in the three-dimensional foot motions of the tibialis posterior dysfunction case compared with normals during walking were consistent with the expected mechanical consequences of a foot without the function of tibialis posterior. The one exception was the inversion of the rearfoot which remained normal. RELEVANCE: Tibialis posterior dysfunction has been recognized as one of the significant impairments of the musculoskeletal system which affects normal walking. Dynamic investigation adds an understanding of how the muscle controls the foot during walking which is essential information for the diagnosis and the adjustment of treatment and rehabilitation for a tibialis posterior dysfunction case.

Adult↗
PubMed2002

Clinical correlates to muscle biopsy findings in HIV patients experiencing fatigue: a case series.

Muscular fatigue may result from HIV infection, and may be associated with antiretroviral drug treatment. Clinical features linked to muscle biopsy findings may assist in determining etiology, and guide treatment decisions. This case series examined HIV patients in an ambulatory HIV clinic who received antiretroviral therapy, and complained of unexplained muscular fatigue. Clinical features with measurement of acid-base status, levels of lactate, aminotransferases, triglycerides and creatine kinase were correlated to light and electron microscopic results of muscle biopsy. Three patients with acquired mitochondrial changes on biopsy shared common features of lactatemia, elevated aminotransferases and triglycerides, and ultrasonographic hepatic steatosis. A fourth patient with normal mitochondria had myositis with fibrosis, but no systemic symptoms. Biochemical parameters were unremarkable, except for a high creatine kinase. Acquired mitochondrial disease may manifest as systemic illness and muscular fatigue. Unique metabolic changes and other organ dysfunction may precede overt physical signs of HIV myopathy.

Adult↗
PubMed2006

Redox modulation of contractile function in respiratory and limb skeletal muscle.

For the last half century, scientists have studied the biological importance of free radicals in respiratory and limb muscles. We now know that muscle fibers continually produce both reactive oxygen species (ROS) and nitric oxide (NO) and that both cascades play critical roles in contractile regulation. Under basal conditions, muscle-derived ROS and NO exert opposing effects. Low-level ROS activity is an essential part of the homeostatic milieu and is required for normal force production whereas NO derivatives function as a brake on the system, limiting force. The modulatory effects of ROS and NO are disrupted by conditions that exaggerate production including mechanical unloading, inflammatory disease, and strenuous exercise. Marked increases in ROS or NO levels cause contractile dysfunction, resulting in muscle weakness and fatigue. These principles provide a foundation for ongoing research to identify the mechanisms of ROS and NO action and develop interventions that protect muscle function.

Acetylcysteine↗
PubMed2004

Exercise-induced increase in skeletal muscle vasodilatory responses in obese Zucker rats.

The purpose of this study was to test the hypothesis that exercise training improves microvascular function in obese Zucker rats, a model of obesity and type II diabetes. Animals were divided into four age-matched groups: lean sedentary (LS), lean exercise (LE), obese sedentary (OS), and obese exercise (OE). The exercise groups were treadmill-exercised from 5 to 11 wk of age, including a 2-wk acclimation period. Mean arterial pressure (MAP) was not significantly different between any of the groups. The OS had significantly higher mean body weight, blood glucose, insulin, IL-6, and leptin levels compared with the LS, whereas the OE had significantly lower blood glucose, insulin, and IL-6 levels compared with the OS. Functional hyperemia and endothelial-dependent vasodilation were tested in the spinotrapezius muscle using intravital microscopy. Functional hyperemia and acetylcholine (0.1 microM, 1 microM, and 10 microM) responses were significantly attenuated in OS compared with the LS, while the contraction and ACh-induced (1 microM and 10 microM) vasodilation were significantly increased in both LE and OE compared with the sedentary animals. These results suggest that exercise training can improve vascular function in this model of type II diabetes. Moreover, the impaired vasodilation observed in 11-wk-old OZR suggests that the microvascular dysfunction is not likely due to an elevated blood pressure.

Acetylcholine↗