Body growth, mitochondrial enzymatic capacities and aspects of the antioxidant system and redox balance under calorie restriction in young turbot (Scophthalmus maximus, L.).

Caloric reduction (cr) without undernutrition has been found to enhance stress resistance and life span in endotherms and ectotherms. We investigated the effect of 30% reduction in food offering on growth, aerobic capacities and oxidative stress parameters in young turbot (Scophthalmus maximus, L.).No differences in body weight, length and hepatosomatic index between the ad libitum fed (AL) and the calorie reduced (CR) group occurred after 55 days of diet application. Of the mitochondrial marker enzymes, only citrate synthase activity in liver was reduced under CR, whereas muscle CS activity and cytochrome oxidase activity in both tissues remained the same in both feeding groups. The concentration of reduced glutathione increased significantly during feeding in muscle of CR fish, resulting in a more reduced glutathione redox ratio (GSH/GSSG) compared to AL fish muscle. TBARS (lipid peroxidation) but not protein carbonyl content (protein oxidation) was significantly reduced in CR fish muscle. Liver oxidative stress parameters did not vary significantly between experimental feeding groups.We conclude that 30% calorie reduction over 8 weeks has no adverse effect on young turbot. On the contrary, cr supports a reduced tissue oxidation state and reduces accumulation of lipid peroxidation products in muscle at sustained muscular aerobic capacity

A Phase 2, Double-Blind, randomized, Dose-Ranging trial Of Reldesemtiv in patients with ALS

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898