ORCID Profile
0000-0003-4403-0490
Current Organisation
University of Nottingham
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Publisher: Public Library of Science (PLoS)
Date: 07-07-2020
Publisher: American Diabetes Association
Date: 17-07-2013
DOI: 10.2337/DB13-0062
Abstract: Low aerobic exercise capacity is a risk factor for diabetes and a strong predictor of mortality, yet some in iduals are “exercise-resistant” and unable to improve exercise capacity through exercise training. To test the hypothesis that resistance to aerobic exercise training underlies metabolic disease risk, we used selective breeding for 15 generations to develop rat models of low and high aerobic response to training. Before exercise training, rats selected as low and high responders had similar exercise capacities. However, after 8 weeks of treadmill training, low responders failed to improve their exercise capacity, whereas high responders improved by 54%. Remarkably, low responders to aerobic training exhibited pronounced metabolic dysfunction characterized by insulin resistance and increased adiposity, demonstrating that the exercise-resistant phenotype segregates with disease risk. Low responders had impaired exercise-induced angiogenesis in muscle however, mitochondrial capacity was intact and increased normally with exercise training, demonstrating that mitochondria are not limiting for aerobic adaptation or responsible for metabolic dysfunction in low responders. Low responders had increased stress/inflammatory signaling and altered transforming growth factor-β signaling, characterized by hyperphosphorylation of a novel exercise-regulated phosphorylation site on SMAD2. Using this powerful biological model system, we have discovered key pathways for low exercise training response that may represent novel targets for the treatment of metabolic disease.
Publisher: BMJ
Date: 12-2009
Publisher: American Physiological Society
Date: 09-2008
DOI: 10.1152/AJPENDO.90411.2008
Abstract: We determined the effects of intravenous infusion of amino acids (AA) at serum insulin of 5, 30, 72, and 167 mU/l on anabolic signaling, expression of ubiquitin-proteasome components, and protein turnover in muscles of healthy young men. Tripling AA availability at 5 mU/l insulin doubled incorporation of [1- 13 C]leucine [i.e., muscle protein synthesis (MPS), P 0.01] without affecting the rate of leg protein breakdown (LPB appearance of d 5 -phenylalanine). While keeping AA availability constant, increasing insulin to 30 mU/l halved LPB ( P 0.05) without further inhibition at higher doses, whereas rates of MPS were identical to that at 5 mU/l insulin. The phosphorylation of PKB Ser 473 and p70 S6k Thr 389 increased concomitantly with insulin, but whereas raising insulin to 30 mU/l increased the phosphorylation of mTOR Ser 2448 , 4E-BP1 Thr 37/46 , or GSK3β Ser 9 and decreased that of eEF2 Thr 56 , higher insulin doses to 72 and 167 mU/l did not augment these latter responses. MAFbx and proteasome C2 subunit proteins declined as insulin increased, with MuRF-1 expression largely unchanged. Thus increasing AA and insulin availability causes changes in anabolic signaling and amounts of enzymes of the ubiquitin-proteasome pathway, which cannot be easily reconciled with observed effects on MPS or LPB.
Publisher: Informa UK Limited
Date: 03-2013
Publisher: American Physiological Society
Date: 06-2010
DOI: 10.1152/JAPPLPHYSIOL.01295.2009
Abstract: A low maximal oxygen consumption (V̇o 2max ) is a strong risk factor for premature mortality. Supervised endurance exercise training increases V̇o 2max with a very wide range of effectiveness in humans. Discovering the DNA variants that contribute to this heterogeneity typically requires substantial s le sizes. In the present study, we first use RNA expression profiling to produce a molecular classifier that predicts V̇o 2max training response. We then hypothesized that the classifier genes would harbor DNA variants that contributed to the heterogeneous V̇o 2max response. Two independent preintervention RNA expression data sets were generated ( n = 41 gene chips) from subjects that underwent supervised endurance training: one identified and the second blindly validated an RNA expression signature that predicted change in V̇o 2max (“predictor” genes). The HERITAGE Family Study ( n = 473) was used for genotyping. We discovered a 29-RNA signature that predicted V̇o 2max training response on a continuous scale these genes contained ∼6 new single-nucleotide polymorphisms associated with gains in V̇o 2max in the HERITAGE Family Study. Three of four novel candidate genes from the HERITAGE Family Study were confirmed as RNA predictor genes (i.e., “reciprocal” RNA validation of a quantitative trait locus genotype), enhancing the performance of the 29-RNA-based predictor. Notably, RNA abundance for the predictor genes was unchanged by exercise training, supporting the idea that expression was preset by genetic variation. Regression analysis yielded a model where 11 single-nucleotide polymorphisms explained 23% of the variance in gains in V̇o 2max , corresponding to ∼50% of the estimated genetic variance for V̇o 2max . In conclusion, combining RNA profiling with single-gene DNA marker association analysis yields a strongly validated molecular predictor with meaningful explanatory power. V̇o 2max responses to endurance training can be predicted by measuring a ∼30-gene RNA expression signature in muscle prior to training. The general approach taken could accelerate the discovery of genetic biomarkers, sufficiently discrete for diagnostic purposes, for a range of physiological and pharmacological phenotypes in humans.
Publisher: Springer Science and Business Media LLC
Date: 08-2014
Publisher: American Physiological Society
Date: 09-2005
DOI: 10.1152/AJPENDO.00092.2005
Abstract: This study investigates the consequences of inhibition of adipose tissue lipolysis on skeletal muscle substrate use. Ten subjects were studied at rest and during exercise and subsequent recovery under normal, fasting conditions (control trial, CON) and following administration of a nicotinic acid analog (low plasma free fatty acid trial, LFA). Continuous [U- 13 C]palmitate and [6,6- 2 H 2 ]glucose infusions were applied to quantify plasma free fatty acid (FFA) and glucose oxidation rates and to estimate intramuscular triacylglycerol (IMTG) and glycogen use. Muscle biopsies were collected to measure 1) fiber type-specific IMTG content 2) allosteric regulators of hormone-sensitive lipase (HSL), glycogen phosphorylase, and pyruvate dehydrogenase and 3) the phosphorylation status of HSL at Ser 563 and Ser 565 . Administration of a nicotinic acid analog (acipimox) substantially reduced plasma FFA rate of appearance and subsequent plasma FFA concentrations ( P 0.0001). At rest, this substantially reduced plasma FFA oxidation rates, which was compensated by an increase in the estimated IMTG use ( P 0.05). During exercise, the progressive increase in FFA rate of appearance, uptake, and oxidation was prevented in the LFA trial and matched by greater IMTG and glycogen use. Differential phosphorylation of HSL or relief of its allosteric inhibition by long-chain fatty acyl-CoA could not explain the increase in muscle TG use, but there was evidence to support the contention that regulation may reside at the level of the glucose-fatty acid cycle. This study confirms the hypothesis that plasma FFA availability regulates both intramuscular lipid and glycogen use in vivo in humans.
Publisher: Elsevier BV
Date: 02-2014
Abstract: Skeletal muscle satellite cells (SCs) play an important role in the myogenic adaptive response to exercise. It remains to be established whether nutrition plays a role in SC activation in response to exercise. In the present study, we assessed whether dietary protein alters the SC response to a single bout of resistance exercise. Twenty healthy young (aged 21 ± 2 y) males were randomly assigned to consume a 4-d controlled diet that provided either 1.2 g protein ⋅ kg body weight(-1) ⋅ d(-1) [normal protein diet (NPD)] or 0.1 g protein ⋅ kg body weight(-1) ⋅ d(-1) [low protein diet (LPD)]. On the second day of the controlled diet, participants performed a single bout of resistance exercise. Muscle biopsies from the vastus lateralis were collected before and after 12, 24, 48, and 72 h of post-exercise recovery. SC content and activation status were determined using immunohistochemistry. Protein and mRNA expression were determined using Western blotting and reverse transcription polymerase chain reaction. The number of myostatin + SCs decreased significantly at 12, 24, and 48 h (range, -14 to -49% P < 0.05) after exercise cessation, with no differences between groups. Although the number of myostatin + SCs returned to baseline in the type II fibers on the NPD after 72 h of recovery, the number remained low on the LPD. At the 48 and 72 h time points, myostatin protein expression was elevated (86 ± 26% and 88 ± 29%, respectively) on the NPD (P < 0.05), whereas it was reduced at 72 h (-36 ± 12% compared with baseline) in the LPD group (P < 0.05). This study demonstrates that dietary protein intake does not modulate the post-exercise increase in SC content but modifies myostatin expression in skeletal muscle tissue. This trial was registered at clinicaltrials.gov as NCT01220037.
Publisher: Wiley
Date: 25-02-2011
Publisher: MDPI AG
Date: 17-12-2021
Abstract: Muscle deconditioning impairs both locomotor function and metabolic health, and is associated with reduced quality life and increased mortality rates. Despite an appreciation of the existence of phenomena such as muscle anabolic resistance, mitophagy, and insulin resistance with age and disease in humans, little is known about the mechanisms responsible for these negative traits. With the complexities surrounding these unknowns and the lack of progress to date in development of effective interventions, there is a need for alternative approaches. Metabolomics is the study of the full array of metabolites within cells or tissues, which collectively constitute the metabolome. As metabolomics allows for the assessment of the cellular metabolic state in response to physiological stimuli, any chronic change in the metabolome is likely to reflect adaptation in the physiological phenotype of an organism. This, therefore, provides a holistic and unbiased approach that could be applied to potentially uncover important novel facets in the pathophysiology of muscle decline in ageing and disease, as well as identifying prognostic markers of those at risk of decline. This review will aim to highlight the current knowledge and potential impact of metabolomics in the study of muscle mass loss and deconditioning in humans and will highlight key areas for future research.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2015
End Date: 2020
Funder: Arthritis Research UK
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