Exercise counteracts lipotoxicity by improving lipid turnover and lipid droplet quality.

The incidence of obesity and metabolic disease, such as type 2 diabetes mellitus (T2D), is rising globally. Dietary lipid over supply leads to lipid accumulation at ectopic sites, such as skeletal muscle. Ectopic lipid storage is highly correlated with insulin resistance and T2D, likely due to a loss of metabolic flexibility - the capacity to switch between fat and glucose oxidation upon insulin stimulation - and cellular dysfunction because of lipotoxicity. However, muscle lipid levels are also elevated in endurance-trained athletes, presenting a paradoxical phenotype of increased intramuscular lipids along with high insulin sensitivity - the 'athletes' paradox'. This review focuses on recent human data to characterize intramuscular lipid species in order to elucidate some of the underlying mechanisms driving skeletal muscle lipotoxicity. There is evidence that lipotoxicity is characterized by an increase in bioactive lipid species, such as ceramide. The athletes' paradox supports the notion that regular physical exercise has health benefits that might originate from the alleviation of lipotoxicity. Indeed, exercise training alleviates intramuscular ceramide content in obese individuals without a necessary decrease in ectopic lipid storage. Furthermore, evidence shows that exercise training elevates markers of lipid droplet dynamics such as the PLIN proteins, and triglyceride lipases ATGL and HSL, as well as mitochondrial efficiency, potentially explaining the improved lipid turnover and a reduction in the accumulation of lipotoxic intermediates observed with the athelets' paradox.

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.

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.