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Chronic heart failure (CHF) induces muscle fiber-type specific alterations in skeletal muscle [O.sub.2] delivery and utilization during metabolic transitions. As a result, the recovery of microvascular P[O.sub.2] ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]) is prolonged in slow-twitch skeletal muscle but not fast-twitch skeletal muscle in rats with CHF. We tested the hypothesis that CHF slows [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] recovery in rat skeletal muscle of a mixed fiber-type analogous to human locomotory muscles and that the degree of slowing correlates with central indexes of heart failure. Healthy control [n = 6, left ventricular end-diastolic pressure (LVEDP): 10 [+ or -] 1 mmHg], moderate CHF (n = 6, LVEDP: 18 [+ or -] 2 mmHg), and severe CHF (n = 4, LVEDP: 34 [+ or -] 2 mmHg) female Sprague-Dawley rats had their fight spinotrapezius muscles (41% type I, 7% type IIa, and 52% type IIb and d/x) exposed, and [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] was measured via phosphorescence quenching during 180 s of recovery from 180 s of electrically induced twitch contractions (1 Hz, 4-6 V). CHF progressively slowed the mean response time (MRT; the time to reach 63% of the overall dynamic response) of [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] recovery ([MRT.sub.off]; control: 60.2 [+ or -] 6.9, moderate CHF: 72.8 [+ or -] 6.6, and severe CHF: 109.8 [+ or -] 6.6 s, P < 0.05 for all). [MRT.sub.off] correlated positively with central hemodynamic (LVEDP: r = 0.76, P < 0.01) and morphological (right ventricle-to-body weight ratio: r = 0.74, P < 0.01; and lung weight-to-body weight ratio: r = 0.79, P < 0.01) indexes of heart failure. The present investigation suggests that slowed [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] kinetics during recovery in CHF constitutes a mechanistic link between impaired circulatory and metabolic recovery after contractions in CHF. skeletal muscle; oxygen delivery; myocardial infarction; left ventricular end-diastolic pressure; phosphorescence quenching; partial pressure of oxygen doi: 10.1152/ajpheart.00590.2010.

Sphingomyelinase (SMase) hydrolyzes membrane sphingomyelin into ceramide, which increases oxidants in nonmuscle cells. Serum SMase activity is elevated in sepsis and heart failure, conditions where muscle oxidants are increased, maximal muscle force is diminished, and fatigue is accelerated. We tested the hypotheses that exogenous SMase and accumulation of ceramide in muscle increases oxidants in muscle cells, depresses specific force of unfatigued muscle, and accelerates the fatigue process. We also anticipated that the antioxidant N-acetylcysteine (NAC) would prevent SMase effects on muscle function. We studied the responses of C2C12 myotubes and mouse diaphragm to SMase treatment in vitro. We observed that SMase caused a 2.8-fold increase in total ceramide levels in myotubes. Exogenous ceramide and SMase elevated oxidant activity in C2C12 myotubes by 15-35% (P < 0.05) and in diaphragm muscle fiber bundles by 58-120% (P < 0.05). The SMase-induced increase in diaphragm oxidant activity was prevented by NAC. Exogenous ceramide depressed diaphragm force by 55% (P < 0.05), while SMase depressed maximal force by 30% (P < 0.05) and accelerated fatigue--effects opposed by treatment with NAC. In conclusion, our findings suggest that SMase stimulates a ceramide-oxidant signaling pathway that results in muscle weakness and fatigue. exercise; oxidative stress; ceramide; diaphragm; inflammation doi: 10.1152/ajpcell.00065.2010.

We investigated the effects of prior heavy exercise on the spatial heterogeneity of muscle deoxygenation kinetics and the relationship to the pulmonary 02 uptake (pV[o.sub.2]) kinetics during subsequent heavy exercise. Seven healthy men completed two 6-min bouts of heavy work rate cycling exercise, separated by 6 min of unloaded exercise. The changes in the concentration of deoxyhemoglobin/myoglobin ([DELTA]deoxy-[Hb+Mb]) were assessed simultaneously at 10 different sites on the rectus femoris muscle using multichannel near-infrared spectroscopy. Prior exercise had no effect on either the time constant or the amplitude of the primary component pV[o.sub.2], whereas it reduced the amplitude of the slow component (SC). [DELTA]Deoxy-[Hb+Mb] across all 10 sites for bout 2 displayed a shorter time delay (mean and SD for subjects: 13.5 [+ or -] 1.3 vs. 9.3 [+ or -] 1.4 s; P < 0.01) and slower primary component time constant ([tau]: 9.3 [+ or -] 1.3 vs. 17.8 [+ or -] 1.0 s; P < 0.01) compared with bout 1. Prior exercise significantly reduced both the intersite coefficient of variation (CV) of the [tau] of [DELTA]deoxy-[Hb+Mb] (26.6 [+ or -] 11.8 vs. 13.7 [+ or -] 5.6%; P < 0.01) and the point-by-point heterogeneity [root mean square error (RMSE)] during the primary component in the second bout. However, neither the change in the CV for [tau] nor RMSE of [DELTA]deoxy-[Hb+Mb] correlated with the reduction in the SC in pV[o.sub.2] kinetics during subsequent heavy exercise. In conclusion, prior exercise reduced the spatial heterogeneity of the primary component of muscle deoxygenation kinetics. This effect was not correlated with alterations in the pV[o.sub.2] response during subsequent heavy exercise. near-infrared spectroscopy; spatial heterogeneity; oxygen uptake kinetics; muscle oxygen delivery

Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of all patients with heart failure and frequently affects postmenopausal women. The HFpEF condition is phenotype-specific, with skeletal myopathy that is crucial for disease development and progression. However, most of the current preclinical models of HFpEF have not addressed the postmenopausal phenotype. We sought to advance a rodent model of postmenopausal HFpEF and examine skeletal muscle abnormalities therein. Female, ovariectomized, spontaneously hypertensive rats (SHRs) were fed a high-fat, high-sucrose diet to induce HFpEF. Controls were female sham-operated Wistar-Kyoto rats on a lean diet. In a complementary, longer-term cohort, controls were female sham-operated SHRs on a lean diet to evaluate the effect of strain difference in the model. Our model developed key features of HFpEF that included increased body weight, glucose intolerance, hypertension, cardiac hypertrophy, diastolic dysfunction, exercise intolerance, and elevated plasma cytokines. In limb skeletal muscle, HFpEF decreased specific force by 15%– 30% (P < 0.05) and maximal mitochondrial respiration by 40%–55% (P < 0.05), increased oxidized glutathione by approximately twofold (P < 0.05), and tended to increase mitochondrial H2O2 emission (P = 0.10). Muscle fiber cross-sectional area, markers of mitochondrial content, and indices of capillarity were not different between control and HFpEF in our short-term cohort. Overall, our preclinical model of postmenopausal HFpEF recapitulates several key features of the disease. This new model reveals contractile and mitochondrial dysfunction and redox imbalance that are potential contributors to abnormal metabolism, exercise intolerance, and diminished quality of life in patients with postmenopausal HFpEF. [ABSTRACT FROM AUTHOR]

Background/Aims: Diaphragm dysfunction with increased reactive oxygen species (ROS) occurs within 72 hrs post-myocardial infarction (MI) in mice and may contribute to loss of inspiratory maximal pressure and endurance in patients. Methods: We used wild-type (WT) and whole-body Nox4 knockout (Nox4KO) mice to measure diaphragm bundle force in vitro with a force transducer, mitochondrial respiration in isolated fiber bundles with an O2 sensor, mitochondrial ROS by fluorescence, mRNA (RT-PCR) and protein (immunoblot), and fiber size by histology 72 hrs post-MI. Results: MI decreased diaphragm fiber cross-sectional area (CSA) (~15%, p = 0.015) and maximal specific force (10%, p = 0.005), and increased actin carbonylation (5-10%, p = 0.007) in both WT and Nox4KO. Interestingly, MI did not affect diaphragm mRNA abundance of MAFbx/atrogin-1 and MuRF-1 but Nox4KO decreased it by 20-50% (p < 0.01). Regarding the mitochondria, MI and Nox4KO decreased the protein abundance of citrate synthase and subunits of electron transport system (ETS) complexes and increased mitochondrial O2 flux (JO2) and H2O2 emission (JH2O2) normalized to citrate synthase. Mitochondrial electron leak (JH2O2/JO2) in the presence of ADP was lower in Nox4KO and not changed by MI. Conclusion: Our study shows that the early phase post-MI causes diaphragm atrophy, contractile dysfunction, sarcomeric actin oxidation, and decreases citrate synthase and subunits of mitochondrial ETS complexes. These factors are potential causes of loss of inspiratory muscle strength and endurance in patients, which likely contribute to the pathophysiology in the early phase post-MI. Whole-body Nox4KO did not prevent the diaphragm abnormalities induced 72 hrs post-MI, suggesting that systemic pharmacological inhibition of Nox4 will not benefit patients in the early phase post-MI. [ABSTRACT FROM AUTHOR]