Nutritional regulation of mitochondrial biogenic energy-sensing pathways in skeletal muscle following endurance exercise

Endurance exercise improves health partly though improvements in skeletal muscle function. Mitochondrial biogenesis is one of the mechanisms that underpin the positive health benefits of endurance exercise. Endurance-exercise and energy sensitive pathways signal to promote transcriptional processes that initiate the adaptive response. Thus the aim of this thesis was to further understand the regulation of post-exercise signalling within skeletal muscle, with specific focus on the activation of energy-sensitive mitochondrial biogenic signalling pathways. It was demonstrated that muscle-specific knockout of p53 does not impair mitochondrial protein content or enzyme activity within mouse skeletal muscle. In human skeletal muscle, fasting and fasted-exercise augment CREB$^S$$^e$$^r$$^1$$^3$$^3$ and AMPK$^T$$^h$$^r$$^1$$^7$$^2$ phosphorylation, while the mRNA expression of $PDK4$ but not $PPARGC1A$ is also increased in the fasted state. Finally, one week of nicotinamide riboside supplementation did not alter skeletal muscle mitochondrial respiration and whole-body substrate utilisation at rest or during endurance exercise, while SIRT1 and 3 activity and $PPARGC1A$ mRNA expression at rest and following endurance-exercise are also unaffected by nicotinamide riboside supplementation. Overall, this thesis contributes novel data to the understanding of metabolism and skeletal muscle signalling following endurance exercise and how nutrition and endurance exercise could be integrated to optimise specific adaptations

Effects of carbohydrate dose and frequency on metabolism, gastrointestinal discomfort and cross-country skiing performance

This study investigated carbohydrate ingestion of varied doses and frequencies during a simulated cross-country skiing time-trial. Ten men and three women (age: 30±7 y; V ̇O2max: 59.6±5.7 mL·kg-1·min-1) completed four, 30-km classic technique roller-skiing time-trials on a treadmill. A 1:1 maltodextrin-fructose carbohydrate solution was provided at high (2.4 g∙min-1; HC) and moderate (1.2 g∙min-1; MC) ingestion rates, each at high (six feeds; HF) and low (two feeds; LF) frequencies. While performance time was not significantly different between trials (140:11±15:31, 140:43±17:40, 139:12±15:32 and 140:33±17:46 min:s in HC-HF, HC-LF, MC-HF and MC-LF, respectively; p>0.05), it was improved with trial order (p<0.001). There was no effect of order on any other variable (p>0.05). In the LF trials blood glucose was elevated following carbohydrate ingestion (at 4 and 19 km) but was reduced at 14 and 29 km compared to HF strategies (p≤0.05). Gastrointestinal discomfort was higher in HC-LF compared with all other trials (p≤0.05). Whole-body lipid oxidation was lower and carbohydrate oxidation was higher in LF compared with HF trials (p≤0.05). Altering carbohydrate dose or frequency does not affect cross-country ski performance. However, low frequency carbohydrate ingestion resulted in poorer maintenance of euglycaemia, reduced lipid oxidation and increased gastrointestinal discomfort

One week of step reduction lowers myofibrillar protein synthesis rates in young men

Purpose Across the lifespan, physical activity levels decrease and time spent sedentary typically increases. However, little is known about the impact that these behavioral changes have on skeletal muscle mass regulation. The primary aim of this study was to use a step reduction model to determine the impact of reduced physical activity and increased sedentary time on daily myofibrillar protein synthesis rates in healthy young men. Methods Eleven men (22 ± 2 yr) completed 7 d of habitual physical activity (HPA) followed by 7 d of step reduction (SR). Myofibrillar protein synthesis rates were determined during HPA and SR using the deuterated water (2H2O) method combined with the collection of skeletal muscle biopsies and daily saliva samples. Gene expression of selected proteins related to muscle mass regulation and oxidative metabolism were determined via real time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results Daily step count was reduced by approximately 91% during SR (from 13,054 ± 2763 steps per day to 1192 ± 330 steps per day; P < 0.001) and this led to an increased contribution of sedentary time to daily activity (73% ± 6% to 90% ± 3%; P < 0.001). Daily myofibrillar protein synthesis decreased by approximately 27% from 1.39 ± 0.32%·d−1 during HPA to 1.01 ± 0.38%·d−1 during SR (P < 0.05). Muscle atrophy F-box and myostatin mRNA expression were upregulated, whereas mechanistic target of rapamycin, p53, and PDK4 mRNA expression were downregulated after SR (P < 0.05). Conclusions One week of reduced physical activity and increased sedentary time substantially lowers daily myofibrillar protein synthesis rates in healthy young men

Skeletal Muscle Fibre-Specific Knockout of p53 Does Not Reduce Mitochondrial Content or Enzyme Activity

Tumour protein 53 (p53) has been implicated in the regulation of mitochondrial biogenesis in skeletal muscle, with whole-body p53 knockout mice displaying impairments in basal mitochondrial content, respiratory capacity, and enzyme activity. This study aimed to determine the effect of skeletal muscle-specific loss of p53 on mitochondrial content and enzyme activity. Mitochondrial protein content, enzyme activity and mRNA profiles were assessed in skeletal muscle of 8-week-old male muscle fibre-specific p53 knockout mice (p53 mKO) and floxed littermate controls (WT) under basal conditions. p53 mKO and WT mice displayed similar content of electron transport chain proteins I-V and citrate synthase enzyme activity in skeletal muscle. In addition, the content of proteins regulating mitochondrial morphology (MFN2, mitofillin, OPA1, DRP1, FIS1), fatty acid metabolism (β-HAD, ACADM, ACADL, ACADVL), carbohydrate metabolism (HKII, PDH), energy sensing (AMPKα2, AMPKβ2), and gene transcription (NRF1, PGC-1α, and TFAM) were comparable in p53 mKO and WT mice (p > 0.05). Furthermore, p53 mKO mice exhibited normal mRNA profiles of targeted mitochondrial, metabolic and transcriptional proteins (p > 0.05). Thus, it appears that p53 expression in skeletal muscle fibres is not required to develop or maintain mitochondrial protein content or enzyme function in skeletal muscle under basal conditions

Modulation of poly-N-acetylglucosamine accumulation within mature Staphylococcus epidermidis biofilms grown in excess glucose

PNAG is a major component of Staphylococcus epidermidis biofilms involved in intercellular adhesion as well as in the interaction of the biofilm with components of the host immune response. Synthesis of PNAG has been found to be regulated by several environmental factors. In the present study, the effect of glucose metabolism-dependent culture medium acidification in PNAG accumulation was evaluated. Established S. epidermidis biofilms were allowed to grow in excess glucose with or without maintained pH conditions. PNAG accumulation in these biofilms was determined by flow cytometry and fluorescence microscopy using wheat germ agglutinin as a fluorescent probe. Biofilms grown in maintained pH conditions presented significantly higher amounts of this polymer as well as higher icaA expression than biofilms grown in acidic pH conditions. Moreover, PNAG accumulation in biofilms grown in non-maintained pH conditions occurred in association with cell death. Overall, we show that glucose metabolism by decreasing the culture pH affects biofilm physiology in respect to PNAG production and cell death. The reported in vitro modulation of PNAG accumulation within S. epidermidis biofilms further highlights the role of environment on determining the biofilm physiological state.(undefined

Application of calcifying bacteria for remediation of stones and cultural heritages

Since ages, architects and artists worldwide have focused on usage of durable stones as marble and limestone for construction of beautiful and magnificent historic monuments as European Cathedrals, Roman, and Greek temples, Taj Mahal etc. But survival of these irreplaceable cultural and historical assets is in question these days due to their degradation and deterioration caused by number of biotic and abiotic factors. These causative agents have affected not only the esthetic appearance of these structures, but also lead to deterioration of their strength and durability. The present review emphasizes about different causative agents leading to deterioration and application of microbially induced calcium carbonate precipitation as a novel and potential technology for dealing with these problems. The study also sheds light on benefits of microbial carbonate binders over the traditional agents and future directions

Insulin resistance and hyperinsulinaemia in the development and progression of cancer

Experimental, epidemiological and clinical evidence implicates insulin resistance and its accompanying hyperinsulinaemia in the development of cancer, but the relative importance of these disturbances in cancer remains unclear. There are, however, theoretical mechanisms by which hyperinsulinaemia could amplify such growth-promoting effects as insulin may have, as well as the growth-promoting effects of other, more potent, growth factors. Hyperinsulinaemia may also induce other changes, particularly in the IGF (insulin-like growth factor) system, that could promote cell proliferation and survival. Several factors can independently modify both cancer risk and insulin resistance, including subclinical inflammation and obesity. The possibility that some of the effects of hyperinsulinaemia might then augment pro-carcinogenic changes associated with disturbances in these factors emphasizes how, rather than being a single causative factor, insulin resistance may be most usefully viewed as one strand in a network of interacting disturbances that promote the development and progression of cancer

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p