IFN-ß-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis.

Dermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down-regulated genes was mitochondria-related. Histochemical, electron microscopy, and in situ oxygraphy analysis showed mitochondrial abnormalities, including increased reactive oxygen species (ROS) production and decreased respiration, which was correlated with low exercise capacities and a type I IFN signature. Moreover, IFN-ß induced ROS production in human myotubes was found to contribute to mitochondrial malfunctions. Importantly, the ROS scavenger N-acetyl cysteine (NAC) prevented mitochondrial dysfunctions, type I IFN-stimulated transcript levels, inflammatory cell infiltrate, and muscle weakness in an experimental autoimmune myositis mouse model. Thus, these data highlight a central role of mitochondria and ROS in DM. Mitochondrial dysfunctions, mediated by IFN-ß induced-ROS, contribute to poor exercise capacity. In addition, mitochondrial dysfunctions increase ROS production that drive type I IFN-inducible gene expression and muscle inflammation, and may thus self-sustain the disease. Given that current DM treatments only induce partial recovery and expose to serious adverse events (including muscular toxicity), protecting mitochondria from dysfunctions may open new therapeutic avenues for DM.

Exercise-induced second-degree atrioventricular block in endurance athletes.

Training induces volume- and time-dependent morphological and functional changes in the heart. Heart rhythm disorders, such as atrial arrhythmia (including atrial fibrillation and atrial flutter), are a well-established consequence of such long-term endurance practice. Although resting bradycardia and first-degree atrioventricular persist in veteran athletes, a higher conduction system impairment has never been reported neither at rest nor during exercise. We report here two cases of Type II second-degree atrioventricular block occurring during exercise in middle-age well-trained athletes. Because animal and human studies suggest that a progressive myocardial fibrosis could explain such phenomenon, long-term training could also have consequences on the conduction pathways.

L-arginine supplementation improves exercise capacity after a heart transplant.

BACKGROUND: Endothelial dysfunction is associated with the decreased exercise capacity observed in heart-transplant (HTx) recipients. L-arginine supplementation (LAS) stimulates the nitric oxide (NO) pathway and restores endothelial function. OBJECTIVE: We compared exercise capacity in healthy subjects and HTx patients and investigated whether chronic LAS might improve exercise capacity and NO/endothelin balance after an HTx. DESIGN: Clinical, echocardiographic, and exercise characteristics were measured in 11 control subjects and 22 HTx recipients. In a prospective, double-blind study, the 22 HTx recipients performed a 6-min exercise [6-min-walk test (6MWT)] and a maximal bicycle exercise test before and after a 6-wk period of placebo intake or LAS. Endothelial function was measured by analyzing blood NO metabolites, endothelin, and the resulting NO/endothelin balance. RESULTS: Exercise capacity decreased after transplantation. Unlike with the placebo intake, 6 wk of LAS improved quality of life in HTx recipients (mean +/- SEM Minnesota Score: from 15.3 +/- 1.3 to 10.6 +/- 1.1; P < 0.001) and their submaximal exercise capacity. The distance walked during the 6MWT increased (from 525 +/- 20 to 580 +/- 20 m; P = 0.002), and the ventilatory threshold during the incremental test was delayed by 1.2 min (P = 0.01). Central factors such as resting stroke volume, systolic pulmonary arterial pressure, cardiac systolodiastolic functions, and heart-rate reserve were not modified, but LAS significantly increased the NO:endothelin ratio (from 2.49 +/- 0.38 to 3.31 +/- 0.39; P = 0.03). CONCLUSION: Oral LAS may be a useful adjuvant therapeutic to improve quality of life and exercise tolerance in HTx recipients.

Chronic but not acute oral L-arginine supplementation delays the ventilatory threshold during exercise in heart failure patients.

The purpose of this study was to determine, in heart failure patients (HF), whether acute or chronic L-arginine supplementation (LAS) might delay the ventilatory threshold (VT) and whether chronic LAS might reduce exercise-induced plasma lactate increase. HF patients undertook 4 cardiopulmonary bicycle exercises tests. The first 3 were maximal without (EX(1)), after acute (EX(2)), or chronic (EX(3)) oral LAS (6 gm twice a day for 6 weeks). The 4th test (EX(4)) performed after chronic LAS, was similar to the first in order to investigate the effect of chronic LAS on circulating lactate levels. Results showed that acute LAS failed to improve both submaximal and maximal exercise capacities. Similarly, maximal exercise capacity remained unmodified after chronic LAS. Nevertheless, chronic LAS delayed significantly the patients' ventilatory threshold. Thus exercise duration prior to VT increased (mean +/- SEM) from 6.04 +/- 0.9 to 7.7 +/- 1.03 min (p = 0.04), resulting in a significant increase in oxygen uptake (1.05 +/- 0.08 to 1.24 +/- 0.12 L.min(-1); p = 0.03), CO(2) release (0.94 +/- 0.10 to 1.2 +/- 0.12 L.min(-1); p = 0.018), minute ventilation (29.31 +/- 2.8 to 34.5 +/- 2.7 L; p = 0.009), and workload (60.7 +/- 9.8 to 78.5 +/- 10.2 watts; p = 0.034). Furthermore, chronic LAS significantly reduced the exercise-induced increase in postexercise plasma lactate concentration (-21 +/- 7%). In conclusion, unlike acute supplementation, chronic LAS significantly delays the ventilatory threshold, and chronic LAS reduces circulating plasma lactate in HF patients. These data suggest that chronic LAS might improve the ability of HF patients to perform their daily-life activities.