Low-Load High Volume Resistance Exercise Stimulates Muscle Protein Synthesis More Than High-Load Low Volume Resistance Exercise in Young Men

BACKGROUND: We aimed to determine the effect of resistance exercise intensity (%1 repetition maximum-1RM) and volume on muscle protein synthesis, anabolic signaling, and myogenic gene expression. METHODOLOGY/PRINCIPAL FINDINGS: Fifteen men (21+/-1 years; BMI=24.1+/-0.8 kg/m2) performed 4 sets of unilateral leg extension exercise at different exercise loads and/or volumes: 90% of repetition maximum (1RM) until volitional failure (90FAIL), 30% 1RM work-matched to 90%FAIL (30WM), or 30% 1RM performed until volitional failure (30FAIL). Infusion of [ring-13C6] phenylalanine with biopsies was used to measure rates of mixed (MIX), myofibrillar (MYO), and sarcoplasmic (SARC) protein synthesis at rest, and 4 h and 24 h after exercise. Exercise at 30WM induced a significant increase above rest in MIX (121%) and MYO (87%) protein synthesis at 4 h post-exercise and but at 24 h in the MIX only. The increase in the rate of protein synthesis in MIX and MYO at 4 h post-exercise with 90FAIL and 30FAIL was greater than 30WM, with no difference between these conditions; however, MYO remained elevated (199%) above rest at 24 h only in 30FAIL. There was a significant increase in AktSer473 at 24h in all conditions (P=0.023) and mTORSer2448 phosphorylation at 4 h post-exercise (P=0.025). Phosporylation of Erk1/2Tyr202/204, p70S6KThr389, and 4E-BP1Thr37/46 increased significantly (P<0.05) only in the 30FAIL condition at 4 h post-exercise, whereas, 4E-BP1Thr37/46 phosphorylation was greater 24 h after exercise than at rest in both 90FAIL (237%) and 30FAIL (312%) conditions. Pax7 mRNA expression increased at 24 h post-exercise (P=0.02) regardless of condition. The mRNA expression of MyoD and myogenin were consistently elevated in the 30FAIL condition. CONCLUSIONS/SIGNIFICANCE: These results suggest that low-load high volume resistance exercise is more effective in inducing acute muscle anabolism than high-load low volume or work matched resistance exercise modes

New insights into the role of age and carcinoembryonic antigen in the prognosis of colorectal cancer

The aim of this study was to verify through relative survival (an estimate of cancer-specific survival) the true prognostic factors of colorectal cancer. The study involved 506 patients who underwent locally radical resection. All the clinical, histological and laboratory parameters were prognostically analysed for both overall and relative survival. This latter was calculated from the expected survival of the general population with identical age, sex and calendar years of observation. Univariate and multivariate analyses were applied to the proportional hazards model. Liver metastases, age, lymph node involvement and depth of bowel wall involvement were independent prognosticators of both overall and relative survival, whereas carcinoembryonic antigen (CEA) was predictive only of relative survival. Increasing age was unfavourably related to overall survival, but mildly protective with regard to relative survival. Three out of the five prognostic factors identified are the cornerstones of the current staging systems, and were confirmed as adequate by the analysis of relative survival. The results regarding age explain the conflicting findings so far obtained from studies considering overall survival only and advise against the adoption of absolute age limits in therapeutic protocols. Moreover, the prechemotherapy CEA level showed a high clinical value

Cataract-Causing Defect of a Mutant γ-Crystallin Proceeds through an Aggregation Pathway Which Bypasses Recognition by the α-Crystallin Chaperone

Background: The transparency of the eye lens depends upon maintenance of the native state of the γ- and β-crystallins, which is aided by the abundant chaperones αA- and αB-crystallin. Mature onset cataract, the leading cause of blindness worldwide, involves the polymerization of covalently damaged or partially unfolded crystallins into light-scattering aggregates. A number of single amino acid substitutions and truncations of γ-crystallins result in congenital cataract in both humans and mice, though in many cases the coupling between the protein alterations and the accumulation of aggregates is poorly defined. Methodology/Principal Findings: We have studied the aggregation properties and chaperone interactions of human γD-crystallin carrying substitutions of two buried core mutants, I90F and V75D, which cause congenital cataract in mice. The in vitro aggregation pathway competing with productive refolding was not altered by either substitution. Furthermore, this aggregation pathway for both mutant proteins–originating from a partially folded intermediate–was efficiently suppressed by αB-crystallin. Thus the cataract pathology was unlikely to be associated with a direct folding defect. The native state of wild-type human γD-crystallin exhibited no tendency to aggregate under physiological conditions. However both I90F and V75D native-like proteins exhibited slow (days) aggregation to high molecular weight aggregates under physiological conditions. The perturbed conformation of I90F was recognized and bound by both αA and αB chaperones. In contrast, the aggregation derived from the perturbed state of V75D was not suppressed by either chaperone, and the aggregating species were not bound by the chaperone. Conclusions/Significance: The cataract phenotype of I90F in mice may be due to premature saturation of the finite α- crystallin pool. The V75D aggregation pathway and its escape from chaperone surveillance and aggregation suppression can account for the congenital cataract pathology of this mutant. Failure of chaperone recognition may be an important source of pathology for many other protein folding defects.National Eye Institute (Grant no. EY015834 )National Institutes of Health (U.S.) (Grant no. GM17980