Skeletal Muscle Metabolic Abnormalities Research Articles

Skeletal Muscle Consequences of Phosphatidylethanolamine Synthesis Deficiency.

The maintenance of phospholipid homeostasis is increasingly being implicated in metabolic health. Phosphatidylethanolamine (PE) is the most abundant phospholipid on the inner leaflet of cellular membranes, and we have previously shown that mice with a heterozygous ablation of the PE synthesizing enzyme, Pcyt2 (Pcyt2+/-), develop obesity, insulin resistance, and NASH. Skeletal muscle is a major determinant of systemic energy metabolism, making it a key player in metabolic disease development. Both the total PE levels and the ratio of PE to other membrane lipids in skeletal muscle are implicated in insulin resistance; however, the underlying mechanisms and the role of Pcyt2 regulation in this association remain unclear. Here, we show how reduced phospholipid synthesis due to Pcyt2 deficiency causes Pcyt2+/- skeletal muscle dysfunction and metabolic abnormalities. Pcyt2+/- skeletal muscle exhibits damage and degeneration, with skeletal muscle cell vacuolization, disordered sarcomeres, mitochondria ultrastructure irregularities and paucity, inflammation, and fibrosis. There is intramuscular adipose tissue accumulation, and major disturbances in lipid metabolism with impaired FA mobilization and oxidation, elevated lipogenesis, and long-chain fatty acyl-CoA, diacylglycerol, and triacylglycerol accumulation. Pcyt2+/- skeletal muscle exhibits perturbed glucose metabolism with elevated glycogen content, impaired insulin signaling, and reduced glucose uptake. Together, this study lends insight into the critical role of PE homeostasis in skeletal muscle metabolism and health with broad implications on metabolic disease development.

Contribution of skeletal muscle-specific microRNA-133b to insulin resistance in heart failure.

Insulin resistance (IR) is one of the hallmarks of heart failure (HF). Abnormalities in skeletal muscle (SM) metabolism have been identified in patients with HF. However, the underlying mechanisms of IR development in SM in HF are poorly understood. Herein, we hypothesize that HF upregulates miR-133b in SM and in turn alters glucose metabolism and the propensity toward IR. Mitochondria isolated from SM of mice with HF induced by transverse aortic constriction (TAC) showed lower respiration and downregulation of muscle-specific components of the tricarboxylic acid (TCA) cycle, AMP deaminase 1 (AMPD1), and fumarate compared with those from control animals. RNA-Seq and subsequent qPCR validation confirmed upregulation of SM-specific microRNA (miRNA), miR-133b, in TAC versus sham animals. miR-133b overexpression alone resulted in significantly lower mitochondrial respiration, cellular glucose uptake, and glycolysis along with lower ATP production and cellular energy reserve compared with the scramble (Scr) in C2C12 cells. miR-133b binds to the 3'-untranslated region (UTR) of KLF15, the transcription factor for the insulin-sensitive glucose transporter, GLUT4. Overexpression of miR-133b lowers GLUT4 and lowers pAkt in presence of insulin in C2C12 cells. Finally, lowering miR-133b in primary skeletal myocytes isolated from TAC mice using antagomir-133b reversed the changes in KLF15, GLUT4, and AMPD1 compared with the scramble-transfected myocytes. Taken together, these data demonstrate a role for SM miR-133b in altered glucose metabolism in HF and suggest the therapeutic potential in HF to improve glucose uptake and glycolysis by restoring GLUT4 abundance. The data uncover a novel mechanism for IR and ultimately SM metabolic abnormalities in patients with HF.NEW & NOTEWORTHY Heart failure is associated with systemic insulin resistance and abnormalities in glucose metabolism but the underlying mechanisms are poorly understood. In the skeletal muscle, the major peripheral site of glucose utilization, we observe an increase in miR-133b in heart failure mice, which reduces the insulin-sensitive glucose transporter (GLUT4), glucose uptake, and metabolism in C2C12 and in myocytes. The antagomir for miR-133b restores GLUT4 protein and markers of metabolism in skeletal myocytes from heart failure mice demonstrating that miR-133b is an exciting target for systemic insulin resistance in heart failure and an important player in the cross talk between the heart and the periphery in the heart failure syndrome.

Targeting Skeletal Muscle Dysfunction With L-Carnitine for the Treatment of Patients With Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a major medical problem and the world's third leading cause of death. COPD is a chronic disease with heterogeneous clinical symptoms, disease progression, and treatment responses. Besides pulmonary symptomatology, the common systemic clinical manifestations are cachexia, muscle weakness, and widespread comorbidities such as cardiovascular diseases, diabetes, osteoporosis, and infections. The adverse effects of pharmaceutical therapies contribute to the difficulty of health risk assessment and management of COPD patients. This review shows how skeletal muscle dysfunction and metabolic abnormalities contribute significantly to COPD patients' symptoms, functional activities, quality of life, and overall disease outcomes. Based on the clinical evidence of L-carnitine and derivatives as metabolic and muscle bioenergetic enhancers, we propose broader research and implementation of this nutraceutical agent as an effective, inexpensive, and safe adjuvant therapeutic for the long-term management of COPD patients. Moreover, we believe the management of COPD as a chronic disease should be shifted from symptomatic reactive pharmaceutical intervention to more constructive and non-toxic approaches using a single or combination of natural and nutritional agents with potential muscle metabolic enhancing and immunomodulating activities to achieve a better overall outcome for the patients in terms of morbidity, mortality, and medical cost-reduction.

Abnormalities of Skeletal Muscle, Adipocyte Tissue, and Lipid Metabolism in Heart Failure: Practical Therapeutic Targets.

Chronic diseases, including heart failure (HF), are often accompanied with skeletal muscle abnormalities in both quality and quantity, which are the major cause of impairment of the activities of daily living and quality of life. We have shown that skeletal muscle abnormalities are a hallmark of HF, in which metabolic pathways involving phosphocreatine and fatty acids are largely affected. Not only in HF, but the dysfunction of fatty acid metabolism may also occur in many chronic diseases, such as arteriosclerosis, as well as through insufficient physical exercise. Decreased fatty acid catabolism affects adenosine triphosphate (ATP) production in mitochondria, via decreased activity of the tricarboxylic acid cycle; and may cause abnormal accumulation of adipose tissue accompanied with hyperoxidation and ectopic lipid deposition. Such impairments of lipid metabolism are in turn detrimental to skeletal muscle, which is hence a chicken-and-egg problem between skeletal muscle and HF. In this review, we first discuss skeletal muscle abnormalities in HF, including sarcopenia; particularly their association with lipid metabolism and adipose tissue. On the other hand, the precise mechanisms involved in metabolic reprogramming and dysfunction are beginning to be understood, and an imbalance of daily nutritional intake of individuals has been found to be a causative factor for the development and worsening of HF. Physical exercise has long been known to be beneficial for the prevention and even treatment of HF. Again, the molecular mechanisms by which exercise promotes skeletal muscle as well as cardiac muscle functions are being clarified by recent studies. We propose that it is now the time to develop more “natural” methods to prevent and treat HF, rather than merely relying on drugs and medical interventions. Further analysis of the basic design of and molecular mechanisms involved in the human body, particularly the inextricable association between physical exercise and the integrity and functional plasticity of skeletal and cardiac muscles is required.

266-LB: Evidence for a Hexosamine Biosynthesis Pathway-Mediated Sp1 Cholesterolgenic Response Being an Early Etiological Factor of Insulin Resistance

Excess plasma membrane cholesterol-mediated cellular insulin resistance has been shown to result from increased hexosamine biosynthesis pathway (HBP) O-GlcNAcylation of the transcription factor Sp1 in 3T3-L1 adipocytes and L6 skeletal muscle myotubes. Here we tested the causal relationship between excess skeletal muscle membrane (SMM) cholesterol and insulin resistance, as well as probed the potential HBP/Sp1 link, in mice fed a Western-style high-fat diet for one week or in mice with targeted skeletal muscle overexpression of glucosamine-fructose aminotransferase (GFAT, the rate-limiting enzyme of the HBP). HF feeding increased SMM cholesterol and impaired GLUT4 regulation, glucose tolerance and insulin sensitivity within one week. These early skeletal muscle and systemic metabolic abnormalities were fully prevented in HF-fed mice treated during the one-week diet challenge with two subcutaneous injections of the cholesterol-depleting agent methyl-β-cyclodextrin. Consistent with in vitro data, an HBP-mediated Sp1 cholesterolgenic response contributing to SMM cholesterol accumulation, the transcription of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, was increased in skeletal muscle from HF-fed mice. Furthermore, treating HF-fed mice during the one-week HF-feeding challenge with mithramycin, an agent that blocks Sp1 binding to DNA, prevented the SMM cholesterol buildup, glucose intolerance, and insulin resistance. Skeletal muscle GFAT overexpression also caused accumulation of SMM cholesterol, glucose intolerance, and insulin resistance.These data suggest that early skeletal muscle insulin resistance in the setting of HF feeding are a consequence of a HBP-mediated Sp1 cholesterolgenic transcriptional response and that targeting this pathway has therapeutic potential for preventing insulin resistance and the development of T2D. Disclosure B.A. Grice: None. J.D. Covert: None. A.M. Kreilach: None. M. Thornburg: None. L. Tackett: None. D. McClain: None. J.S. Elmendorf: None. Funding American Diabetes Association (1-15-BS-053 to J.S.E.); National Institutes of Health (R01DK114222-01A1, UL1TR001108T32, DK064466, T32GM077229, P30DK097512); Indiana University-Purdue University; Indianapolis Research Support Funds

Skeletal Muscle Dysfunction and Metabolic Abnormalities in Individuals with Familial Partial Lipodystrophy Is Associated with Diminished Mitochondrial Fatty Acid Oxidation

Background: Familial Partial Lipodystrophy, Dunnigan variety (FPLD) is characterized by post-natal fat loss leading to severe insulin resistance. Affected individuals also display striking skeletal muscle hypertrophy, but there is limited information on muscle function and energy metabolism. We therefore systematically investigated muscle and mitochondrial function in 6 individuals with FPLD and 6 matched controls. Methods: Body composition and intramyocellular lipid content (IMCL) were assessed by DEXA and magnetic resonance spectroscopy, respectively. Maximal voluntary strength and fatigue were assessed for both recumbent leg press and seated chest press. Vastus lateralis muscle biopsies were obtained prior to and following a high fat (40%) mixed-meal. Oxygen consumption in isolated mitochondria was measured using substrates supporting carbohydrate or lipid-based respiration. Insulin Sensitivity Index (SI) was calculated by minimal modelling. Results: Individuals with FPLD had significantly lower SI, lower body fat content, and higher lean mass. Peak leg press and chest press force were not different, but FPLD individuals had earlier fatigue during chest press (number of repetitions: 15 ± 0.6 vs. 20 ± 0.3, p = 0.01). They also had a 50-60% decrease in state 3 respiration measured using substrates supporting lipid-based respiration (p = 0.04). Further, mitochondrial oxidative capacity showed a strong correlation with muscle fatigue (r = 0.76, p = 0.003), and inversely correlated with fasting and post-prandial lipemia and measures of insulin resistance. Conclusion: Individuals with FPLD have higher lean body mass and lower insulin sensitivity. Despite preserved peak muscle strength, they demonstrated earlier muscle fatigue. Decreased mitochondrial fatty acid oxidative capacity, likely related to elevated IMCL, may contribute to muscular and metabolic abnormalities. Disclosure V. Simha: None. I.R. Lanza: None. N. LeBrasseur: None. K. Klaus: None. J. Port: None. M.C. Laurenti: Other Relationship; Self; GlySens Incorporated. C. Cobelli: Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Novo Nordisk Inc.. K. Nair: None.

Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease.

Unacylated ghrelin (UnAG) may lower skeletal muscle oxidative stress, inflammation, and insulin resistance in lean and obese rodents. UnAG-induced autophagy activation may contribute to these effects, likely involving removal of dysfunctional mitochondria (mitophagy) and redox state maintenance. In chronic kidney disease (CKD) oxidative stress, inflammation and insulin resistance may negatively influence patient outcome by worsening nutritional state through muscle mass loss. Here we show in a 5/6 nephrectomy (Nx) CKD rat model that 4 d s.c. UnAG administration (200 µg twice a day) normalizes CKD-induced loss of gastrocnemius muscle mass and a cluster of high tissue mitochondrial reactive oxygen species generation, high proinflammatory cytokines, and low insulin signaling activation. Consistent with these results, human uremic serum enhanced mitochondrial reactive oxygen species generation and lowered insulin signaling activation in C2C12 myotubes while concomitant UnAG incubation completely prevented these effects. Importantly, UnAG enhanced muscle mitophagy in vivo and silencing RNA-mediated autophagy protein 5 silencing blocked UnAG activities in myotubes. UnAG therefore normalizes CKD-induced skeletal muscle oxidative stress, inflammation, and low insulin signaling as well as muscle loss. UnAG effects are mediated by autophagy activation at the mitochondrial level. UnAG administration and mitophagy activation are novel potential therapeutic strategies for skeletal muscle metabolic abnormalities and their negative clinical impact in CKD.-Gortan Cappellari, G., Semolic, A., Ruozi, G., Vinci, P., Guarnieri, G., Bortolotti, F., Barbetta, D., Zanetti, M., Giacca, M., Barazzoni, R. Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease.

Analysis of Skeletal Muscle Torque Capacity and Circulating Ceramides in Patients with Advanced Heart Failure

BackgroundHeart failure (HF)-related exercise intolerance is thought to be perpetuated by peripheral skeletal muscle functional, structural, and metabolic abnormalities. We analyzed specific dynamics of muscle contraction in patients with HF compared with healthy, sedentary controls. MethodsIsometric and isokinetic muscle parameters were measured in the dominant upper and lower limbs of 45 HF patients and 15 healthy age-matched controls. Measurements included peak torque normalized to body weight, work normalized to body weight, power, time to peak torque, and acceleration and deceleration to maximum strength times. Body morphometry (dual energy X-ray absorptiometry scan) and circulating fatty acids and ceramides (lipodomics) were analyzed in a subset of subjects (18 HF and 9 controls). ResultsExtension and flexion time-to-peak torque was longer in the lower limbs of HF patients. Furthermore, acceleration and deceleration times in the lower limbs were also prolonged in HF subjects. HF subjects had increased adiposity and decreased lean muscle mass compared with controls. Decreased circulating unsaturated fatty acids and increased ceramides were found in subjects with HF. ConclusionsDelayed torque development suggests skeletal muscle impairments that may reflect abnormal neuromuscular functional coupling. These impairments may be further compounded by increased adiposity and inflammation associated with increased ceramides.

Dietary combination of sucrose and linoleic acid causes skeletal muscle metabolic abnormalities in Zucker fatty rats through specific modification of fatty acid composition.

A dietary combination of sucrose and linoleic acid strongly contributes to the development of metabolic disorders in Zucker fatty rats. However, the underlying mechanisms of the metabolic disorders are poorly understood. We hypothesized that the metabolic disorders were triggered at a stage earlier than the 8 weeks we had previously reported. In this study, we investigated early molecular events induced by the sucrose and linoleic acid diet in Zucker fatty rats by comparison with other combinations of carbohydrate (sucrose or palatinose) and fat (linoleic acid or oleic acid). Skeletal muscle arachidonic acid levels were significantly increased in the sucrose and linoleic acid group compared to the other dietary groups at 4 weeks, while there were no obvious differences in the metabolic phenotype between the groups. Expression of genes related to arachidonic acid synthesis was induced in skeletal muscle but not in liver and adipose tissue in sucrose and linoleic acid group rats. In addition, the sucrose and linoleic acid group exhibited a rapid induction in endoplasmic reticulum stress and abnormal lipid metabolism in skeletal muscle. We concluded that the dietary combination of sucrose and linoleic acid primarily induces metabolic disorders in skeletal muscle through increases in arachidonic acid and endoplasmic reticulum stress, in advance of systemic metabolic disorders.

Effects of oral amino Acid supplements on functional capacity in patients with chronic heart failure.

Amino acids (AAs) availability is reduced in patients with heart failure (HF) leading to abnormalities in cardiac and skeletal muscle metabolism, and eventually to a reduction in functional capacity and quality of life. In this study, we investigate the effects of oral supplementation with essential and semi-essential AAs for three months in patients with stable chronic HF. The primary endpoints were the effects of AA’s supplementation on exercise tolerance (evaluated by cardiopulmonary stress test and six minutes walking test (6MWT)), whether the secondary endpoints were change in quality of life (evaluated by Minnesota Living with Heart Failure Questionnaire—MLHFQ) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. We enrolled 13 patients with chronic stable HF on optimal therapy, symptomatic in New York Heart Association (NYHA) class II/III, with an ejection fraction (EF) <45%. The mean age was 59 ± 14 years, and 11 (84.6%) patients were male. After three months, peak VO2 (baseline 14.8 ± 3.9 mL/minute/kg vs follow-up 16.8 ± 5.1 mL/minute/kg; P = 0.008) and VO2 at anaerobic threshold improved significantly (baseline 9.0 ± 3.8 mL/minute/kg vs follow-up 12.4 ± 3.9 mL/minute/kg; P = 0.002), as the 6MWT distance (baseline 439.1 ± 64.3 m vs follow-up 474.2 ± 89.0 m; P = 0.006). However, the quality of life did not change significantly (baseline 21 ± 14 vs follow-up 25 ± 13; P = 0.321). A non-significant trend in the reduction of NT-proBNP levels was observed (baseline 1502 ± 1900 ng/L vs follow-up 1040 ± 1345 ng/L; P = 0.052). AAs treatment resulted safe and was well tolerated by all patients. In our study, AAs supplementation in patients with chronic HF improved exercise tolerance but did not change quality of life.

Effect of chronic heart failure on mitochondrial function and apoptotic susceptibility in rat skeletal muscle

Chronic heart failure (CHF) is marked by myocardial dysfunction and is also associated with skeletal muscle metabolic abnormalities but the underlying cellular mechanisms are not well understood. Thus, we investigated whether CHF alters mitochondrial function/content and apoptotic susceptibility in skeletal muscle. Young Lewis rats (8 wks) were subjected to either myocardial infarction to induce CHF or, Sham (Sh) operation, and hindlimb muscles were removed 16‐weeks post‐surgery (n=6/group). Mitochondrial function tended to be impaired in CHF as indicated by a reduced respiratory control ratio (RCR‐State 3/4 respiration). CHF‐induced impairments in respiration coincided with significant reductions in cytochrome c and the mitochondrial anti‐oxidant, MnSOD, in isolated mitochondria. Additionally, oxidative damage, indicated by protein carbonylation was significantly elevated in CHF. CHF animals tended to exhibit greater mitochondrial apoptotic susceptibility (Bax:Bcl‐2) but this surprisingly did not alter the vulnerability to exogenous H2O2‐ induced pro‐apoptotic release from isolated mitochondria. Our preliminary results indicate CHF impairs mitochondrial function and/or content, increases mitochondrial apoptotic susceptibility and enhances ROS‐induced damage in muscle, and these deleterious mitochondrial‐associated adaptations likely contribute towards CHF pathogenesis.

Impaired Aerobic Capacity and Physical Functional Performance in Older Heart Failure Patients With Preserved Ejection Fraction: Role of Lean Body Mass

Exercise intolerance is the primary chronic symptom in patients with heart failure and preserved ejection fraction (HFPEF), the most common form of heart failure in older persons, and can result from abnormalities in cardiac, vascular, and skeletal muscle, which can be further worsened by physical deconditioning. However, it is unknown whether skeletal muscle abnormalities contribute to exercise intolerance in HFPEF patients. This study evaluated lean body mass, peak exercise oxygen consumption (VO2), and the short physical performance battery in 60 older (69 ± 7 years) HFPEF patients and 40 age-matched healthy controls. In HFPEF versus healthy controls, peak percent total lean mass (60.1 ± 0.8% vs. 66.6 ± 1.0%, p < .0001) and leg lean mass (57.9 ± 0.9% vs. 63.7 ± 1.1%, p = .0001) were significantly reduced. Peak VO2 was severely reduced including when indexed to leg lean mass (79.3 ± 18.5 vs. 104.3 ± 20.4 ml/kg/min, p < .0001). Peak VO2 was correlated with percent total (r = .51) and leg lean mass (.52, both p < .0001). The slope of the relationship of peak VO2 with percent leg lean mass was markedly reduced in HFPEF (11 ± 5 ml/min) versus healthy controls (36 ± 5 ml/min; p < .001). Short physical performance battery was reduced (9.9 ± 1.4 vs. 11.3 ± 0.8) and correlated with peak VO2 and total and leg lean mass (all p < .001). Older HFPEF patients have significantly reduced percent total and leg lean mass and physical functional performance compared with healthy controls. The markedly decreased peak VO2 indexed to lean body mass in HFPEF versus healthy controls suggests that abnormalities in skeletal muscle perfusion and/or metabolism contribute to the severe exercise intolerance in older HFPEF patients.

PC-FACS

PC-FACS

AMP‐activated protein kinase control of fat metabolism in skeletal muscle

AMP-activated protein kinase (AMPK) has emerged as a key regulator of skeletal muscle fat metabolism. Because abnormalities in skeletal muscle metabolism contribute to a variety of clinical diseases and disorders, understanding AMPK's role in the muscle is important. It was originally shown to stimulate fatty acid (FA) oxidation decades ago, and since then much research has been accomplished describing this role. In this brief review, we summarize much of these data, particularly in relation to changes in FA oxidation that occur during skeletal muscle exercise. Potential roles for AMPK exist in regulating FA transport into the mitochondria via interactions with acetyl-CoA carboxylase, malonyl-CoA decarboxylase, and perhaps FA transporter/CD36 (FAT/CD36). Likewise, AMPK may regulate transport of FAs into the cell through FAT/CD36. AMPK may also regulate capacity for FA oxidation by phosphorylation of transcription factors such as CREB or coactivators such as PGC-1alpha.

Rebuttal from Dr. Andreassen

Rebuttal from Dr. Andreassen

Counterpoint: Cardiac denervation does not play a major role in exercise limitation after heart transplantation

Despite a successful replacement of the failing heart, heart transplant recipients (Htx) generally demonstrate persistent exercise capacity limitations compared with matched sedentary subjects ([4][1], [16][2], [22][3]). Both central (cardiac and pulmonary dysfunctions) and peripheral (endothelial

Chronic oral ascorbic acid therapy worsens skeletal muscle metabolism in patients with chronic heart failure

Chronic heart failure (CHF) is associated with abnormalities of skeletal muscle metabolism. This may be due to impaired oxygen delivery as a result of endothelial dysfunction. We postulated that ascorbic acid would improve oxygen delivery to exercising muscle and improve skeletal muscle metabolism. We studied skeletal muscle metabolism using (31)P magnetic resonance spectroscopy in 39 CHF patients. Endothelial function was assessed by changes in pulse wave velocity. Subjects were randomised to receive 4 g ascorbic acid daily for 4 weeks in a placebo-controlled double-blind study. Ascorbic acid significantly increased phosphocreatine utilization during exercise. In addition, glycolytic ATP synthesis increased in the ascorbic acid group (change in rate of ATP synthesis at 1 min -0.21+/-0.76 with placebo, 2.06+/-0.60 following ascorbic acid; p<0.05). Phosphocreatine and ADP recovery after exercise were not changed. The fall in pulse wave velocity during reactive hyperaemia was increased by ascorbic acid from -6.3+/-2.6% to -12.1+/-2.0% (p<0.05). These findings suggest that ascorbic acid increased both phosphocreatine utilization and glycolytic ATP synthesis during exercise in patients with CHF implying worsened skeletal muscle metabolism despite improvements in endothelial function.

心血管疾患における電気刺激療法の新たな展開

Electrical stimulation (ES) is an established method for providing muscle activity. Moreover, there are some reports that ES induces angiogenesis. It was thought that the angiogenesis from ES is induced by physical phenomenon such as calculated shear stress, capillary wall tension, and stretch. However, there is a report that the electrical field itself might play a role in angiogenesis by stimulating the vascular endothelial growth factor (VEGF) receptor signaling pathway. Therefore, there is a possibility that ES might be used as a new therapy for ischemic diseases such as arteriosclerosis obliterans (ASO). The limited physical performance of chronic heart failure (CHF) patients may not only be entirely due to impairment of cardiac and lung function but may also result from peripheral hemodynamic variables and abnormalities in skeletal muscle metabolism and structure, such as a decrease in capillary density, mitochondrial content etc. There are some studies showing the positive effect of low frequency electrical stimulation on muscle strength and blood flow in patients who have advanced CHF and can not achieve conventional exercise training. Thus, ES could be recommended for the treatment of patients with severe CHF. Furthermore, cardiac-resynchronization therapy in the form of biventricular stimulation with a pacemaker would reduce the risk of death and hospitalization among patients with advanced CHF. Further studies are required to precisely define the underlying mechanism and determine the most effective mode of application.

Knee-extensor Exercise and Skeletal Muscle Citrate Synthase Activity in COPD Patients

0254 Measured citrate synthase activity (CSA) in skeletal muscle increases after an acute bout of exercise in young healthy adults. PURPOSE: To evaluate CSA levels in COPD patients after acute single-leg knee-extensor exercise (KE) and chronic KE training. METHODS: Muscle biopsies from 13 COPD patients (65 +/− 3yr; FEV1 = 0.95 +/− 0.08L) and 7 age (64 +/− 3yr) and activity level-matched controls were assessed for CSA before and after acute KE. A subgroup of COPD patients (n = 5) completed an 8-week KE training protocol and underwent a second set of biopsy protocol. RESULTS: Resting CSA in all COPD patients was not different from controls (10.64 +/− 1.12 vs. 12.66 +/− 1.50 μmol/min/g). As anticipated, the controls exhibited a 19 +/− 6% increase in CSA after acute KE. In contrast, the untrained COPD patients significantly decreased CSA by 14 +/− 10.3% after acute KE. Post training COPD patients performed acute KE as in the pre-training study, but no longer revealed a significant fall in CSA (10 +/− 7.5%). COPD patients revealed significant plasticity in response to chronic KE training, resulting in increasing CSA from 8.16 +/− 1.7 to 12.69 +/− 2.2. CONCLUSION: Unlike healthy controls, which increased CSA after acute KE, the COPD patients actually decreased CSA. Exercise training improves CSA in COPD and tends to attenuate the fall in CSA because of acute exercise. Although in healthy subjects the exact mechanism by which exercise increases CSA is unknown, these data support the concept that subtle abnormalities in skeletal muscle metabolism accompany COPD. Supported by NIH Grants 1-R25-GM60202 and HL 17731.

Preserved response of mitochondrial function to short-term endurance training in skeletal muscle of heart transplant recipients

ObjectivesWe sought to determine whether intrinsic mitochondrial function and regulation were altered in heart transplant recipients (HTRs) and to investigate the response of mitochondrial function to six-week endurance training in these patients. BackgroundDespite the normalization of central oxygen transport during exercise, HTRs are still characterized by limited exercise capacity, which is thought to result from skeletal muscle metabolic abnormalities. MethodsTwenty HTRs agreed to have vastus lateralis biopsies and exercise testing: before and after training for 12 of them and before and after the same control period for eight subjects unwilling to train. Mitochondrial respiration was evaluated on saponin-permeabilized muscle fibers in the absence or presence (maximum respiration rate [Vmax]) of saturating adenosine diphosphate. ResultsMitochondrial function was preserved at the level of sedentary subjects in untrained HTRs, although they showed 28 ± 5% functional aerobic impairment (FAI). After training, Vmax, citrate synthase, cytochrome coxidase, and mitochondrial creatine kinase (CK) activities were significantly increased by 48%, 40%, 67%, and 53%, respectively (p < 0.05), whereas FAI decreased to 12 ± 5% (p < 0.01). The control of mitochondrial respiration by creatine and mitochondrial CK was also improved (p < 0.01), suggesting that phosphocreatine synthesis and transfer by the mitochondrial CK become coupled to oxidative phosphorylation, as shown in trained, healthy subjects. ConclusionsIn HTRs, the mitochondrial properties of skeletal muscle were preserved and responded well to training, reaching values of physically active, healthy subjects. This suggests that, in HTRs, immunosuppressive drugs do not alter the intrinsic muscle oxidative capacities and that the patients’ physical handicap results from nonmitochondrial mechanisms.