Striated muscle activator of Rho signalling (STARS) is reduced in ageing human skeletal muscle and targeted by miR-628-5p.

AIM: The striated muscle activator of Rho signalling (STARS) is a muscle-specific actin-binding protein. The STARS signalling pathway is activated by resistance exercise and is anticipated to play a role in signal mechanotransduction. Animal studies have reported a negative regulation of STARS signalling with age, but such regulation has not been investigated in humans. METHODS: Ten young (18-30 years) and 10 older (60-75 years) subjects completed an acute bout of resistance exercise. Gene and protein expression of members of the STARS signalling pathway and miRNA expression of a subset of miRNAs, predicted or known to target members of STARS signalling pathway, were measured in muscle biopsies collected pre-exercise and 2 h post-exercise. RESULTS: For the first time, we report a significant downregulation of the STARS protein in older subjects. However, there was no effect of age on the magnitude of STARS activation in response to an acute bout of exercise. Finally, we established that miR-628-5p, a miRNA regulated by age and exercise, binds to the STARS 3'UTR to directly downregulate its transcription. CONCLUSION: This study describes for the first time the resistance exercise-induced regulation of STARS signalling in skeletal muscle from older humans and identifies a new miRNA involved in the transcriptional control of STARS.

Associations of sedentary time patterns and TV viewing time with inflammatory and endothelial function biomarkers in children.

OBJECTIVE: Investigate associations of TV viewing time and accelerometry-derived sedentary time with inflammatory and endothelial function biomarkers in children. METHODS: Cross-sectional analysis of 164 7-10-year-old children. TV viewing time was assessed by parental proxy report and total and patterns of sedentary time accumulation (e.g. prolonged bouts) were assessed by accelerometry. C-reactive protein (CRP), homeostasis model assessment of insulin resistance, interleukin-2, -6, -8, -10, tumour necrosis factor alpha, adiponectin, resistin, brain-derived neurotrophic factor, soluble intercellular and vascular adhesion molecule 1, plasminogen activator inhibitor 1 and soluble E-selectin were assessed. Generalised linear models assessed the associations of TV viewing and sedentary time with biomarkers, adjusting for sex, waist circumference, moderate- to vigorous-intensity physical activity and diet density. RESULTS: Each additional h week(-1) of TV viewing was associated with 4.4% (95% CI: 2.1, 6.7) greater CRP and 0.6% (0.2, 1.0) greater sVCAM-1 in the fully adjusted model. The association between frequency and duration of 5-10 min bouts of sedentary time and CRP was positive after adjustment for sex and waist circumference but attenuated after adjustment for diet density. CONCLUSIONS: This study suggests that TV viewing was unfavourably associated with several markers of inflammation and endothelial dysfunction. The detrimental association between 5 and 10 min bouts of sedentary time and CRP approached significance, suggesting that further research with a stronger study design (longitudinal and/or experimental) is needed to better understand how the accumulation of sedentary time early in life may influence short and longer term health.

Delving into disability in Crohn's disease: dysregulation of molecular pathways may explain skeletal muscle loss in Crohn's disease.

BACKGROUND/AIMS: In Crohn's disease (CD), skeletal muscle mass and function are reduced compared to healthy controls, potentially resulting in disability. Mechanisms contributing to muscle impairment, and thus potential therapeutic targets, are poorly understood. This study aimed to measure and compare skeletal muscle size and molecular targets involved in skeletal muscle growth, in CD subjects and healthy controls. METHODS: CD (n=27) and healthy (n=22) subjects were recruited from the IBD outpatient clinic and via local advertisement respectively. Demographics and clinical data were collected via survey and interview. Quadriceps muscle cross-sectional area was measured using peripheral quantitative CT scanning. Levels of muscle hypertrophy and atrophy signalling targets using quantitative PCR and western blotting were measured in muscle biopsies. RESULTS: Muscle size was 14% lower (p=0.055) and a 54% lower phosphorylated:total (p:t) Akt ratio was measured in the muscle samples (p<0.05), indicating an attenuated muscle hypertrophy pathway in CD compared with controls. In those with CD, a lower p:t Akt ratio (<0.97) was associated with lower serum vitamin D3, lower physical activity indices (49 vs 64 mmol/L, 1.7 vs 2.2×10(6) accelerometer counts respectively, each p<0.05) and a trend towards lower serum ferritin levels (128 vs 322mg/L, p=0.07), compared with CD subjects with normal/high p:t Akt ratios. CONCLUSION: The reduced muscle mass in CD may be explained, in part, by impaired activation of muscle protein synthesis pathways, notably the IGF1-Akt pathway. Normal vitamin D levels and regular exercise may be protective in CD against this trend, though confirmatory longitudinal studies are needed.

Objectively measured muscle fatigue in Crohn's disease: correlation with self-reported fatigue and associated factors for clinical application.

BACKGROUND & AIMS: The association of fatigue with decreased physical performance and underlying mechanisms are poorly understood in Crohn's disease (CD). We aimed to measure and compare self-reported fatigue with skeletal muscle fatigue in CD subjects and healthy controls, and to identify associated factors that may be amenable to change. METHODS: Demographic and clinical data were collected and fatigue assessed using the Fatigue Impact Scale (FIS) in 27 consecutive CD patients and 22 matched healthy controls. Circulating cytokines and growth factors were measured. The rate of quadriceps muscle fatigue was assessed using an isokinetic dynamometer as the decrement of force with 30 contractions performed over a 5-minute period. RESULTS: Compared with healthy controls, CD patients reported greater levels of fatigue (mean global FIS score 45.3 vs 10.5, physical dimension score 12.3 vs 2.7 respectively; each p<0.01) and muscle fatigue (-5.2 vs -1.3 Nm min(-1); p<0.05). The two indices were correlated (r = -0.52 in CD; p<0.01). Patients with CD had lower mean serum IGF-1 levels (16.1 vs 25.4 pmol/L, p<0.01) and higher oxidative stress (TBARS assay 4.3 vs 3.9 µM, p<0.05). On multivariate analysis, low serum vitamin D, IGF-1 and magnesium, and higher IL-6 levels were associated with increased muscle fatigue (all p ≤ 0.05). CONCLUSION: Subjects with CD had more muscle fatigue than matched healthy controls and this correlated well with self-reported fatigue. Of circulating factors that were independently associated with increased muscle fatigue, vitamin D, magnesium and IGF-1 could be targeted in future studies to reduce fatigue and improve physical performance.

Infusion with the antioxidant N-acetylcysteine attenuates early adaptive responses to exercise in human skeletal muscle.

AIM: Production of reactive oxygen species (ROS) in skeletal muscle is markedly increased during exercise and may be essential for exercise adaptation. We, therefore, investigated the effects of infusion with the antioxidant N-acetylcysteine (NAC) on exercise-induced activation of signalling pathways and genes involved in exercise adaptation in human skeletal muscle. METHODS: Subjects completed two exercise tests, 7 days apart, with saline (control, CON) or NAC infusion before and during exercise. Exercise tests comprised of cycling at 71% VO(2peak) for 45 min, and then 92% VO(2peak) to fatigue, with vastus lateralis biopsies at pre-infusion, after 45-min cycling and at fatigue. RESULTS: Analysis was conducted on the mitogen-activated protein kinase signalling pathways, demonstrating that NAC infusion blocked the exercise-induced increase in JNK phosphorylation, but not ERK1/2, or p38 MAPK. Nuclear factor-κB p65 phosphorylation was unaffected by exercise; however, it was reduced in NAC at fatigue by 14% (P < 0.05) compared with pre-infusion. Analysis of exercise and/or ROS-sensitive genes demonstrated that exercise-induced mRNA expression is ROS dependent of MnSOD, but not PGC-1α, interleukin-6, monocyte chemotactic protein-1, or heat-shock protein 70. CONCLUSION: These results suggest that inhibition of ROS attenuates some skeletal muscle cell signalling pathways and gene expression involved in adaptations to exercise.