Biology subjects

Philp, A.

Publications and source records attributed to Philp, A..

15 recordsLinked to original sources

bioRxiv2026

Ageing blunts the phospho-proteomic response to resistance exercise in humans

Ageing blunts the adaptive growth response in human skeletal muscle. To define the molecular processes underlying this impairment, we performed unbiased analysis of the phosphoproteome and total proteome in healthy young and old human skeletal muscle following acute resistance exercise (ResEX) and essential amino acid (EAA) ingestion. Ageing led to global suppression of the growth-induced global phosphoproteome, despite intact mTORC1 activation in old muscle. Our results identify widespread effects of ageing on skeletal muscle growth and highlight novel pathways for therapeutic development in aged skeletal muscle.

physiology↗

bioRxiv2026

A decline in skeletal muscle NOX4 abrogates adaptive homeostasis and exacerbates ageing

A decline in NFE2L2-orchestrated adaptive homeostasis and oxidative distress are thought to be key features of ageing. In contracting skeletal muscle, the ROS-producing enzyme NADPH oxidase 4 (NOX4) is a potent inducer of NFE2L2 adaptive homeostasis. Here we report that skeletal muscle NOX4 levels decline in aged mice and humans, resulting in abrogated NFE2L2 adaptive homeostasis, increased protein oxidative damage and decreased muscle function. We show that deleting NOX4 in skeletal muscle exacerbates the physiological decline associated with ageing, resulting in overt sarcopenia and frailty, characterised by physical inactivity, increased adiposity, systemic inflammation, whole-body insulin resistance and advanced liver disease in aged chow-fed mice. The systems-wide physiological decline in aged skeletal muscle NOX4-deficient mice could be corrected by activating NFE2L2 with sulforaphane and reinstating adaptive homeostatic responses otherwise induced by exercise. Our findings provide important insights into the basis for the decline in NFE2L2-orchestrated adaptive homeostasis with age and identify key mechanisms by which exercise may promote healthy ageing.

physiology↗

bioRxiv2025

Exercise training improves sarcopenic muscle function via restoration of mitochondrial quality control

Mitophagy is an essential component of the mitochondrial quality control program, maintaining mitochondrial homeostasis in metabolic tissues such as skeletal muscle. With age, it is thought that mitochondrial quality control becomes dysregulated, leading to the progression of age-associated diseases such as sarcopenia. Exercise is known to enhance skeletal muscle mitochondrial health and may be an effective intervention to prevent sarcopenia, however the role of mitophagy in this process is unknown. Utilising mitophagy reporter mice (mito-QC), we assessed adaptations in skeletal muscle mitophagy in response to increased age (3-26 months) and following an 8-week endurance exercise training period. Immunofluorescent imaging revealed that ageing led to an accumulation of mitolysosomes in sarcopenic old mice indicative of increased mitophagy, an adaptive response that was reversed by exercise training. In parallel to reducing age-associated mitophagy, exercise training increased mitochondrial respiratory capacity and improved muscle strength, suggesting that alterations in mitochondrial quality control led to improvements in skeletal muscle function. Exercise-mediated alterations in mitophagy were accompanied by increases in BNIP3, FUNDC1 and BCL2L13 protein content post training. Collectively our data suggests that sarcopenia leads to dysregulation of mitophagy in skeletal muscle. Restoring mitophagy balance with exercise training leads to improvements in mitochondrial respiration and skeletal muscle strength, identifying a novel cellular mechanism to explain the benefits of exercise training in old age.

cell biology↗

bioRxiv2025

Mitochondrial uncoupler BAM15 improves skeletal muscle function and mitochondrial respiration in Sarcopenia

BackgroundAgeing is accompanied by progressive declines in skeletal muscle mass and strength, culminating in sarcopenia, a condition that contributes to frailty, multimorbidity, and mortality. Age-related changes to mitochondria lead to oxidative damage and dysfunction and are proposed to occur early in the trajectory of sarcopenia, supporting the candidacy of mitochondrial-protective therapies. Here, we test the efficacy of mitochondrial uncoupler BAM15 in age-dependent sarcopenic mouse models. MethodsMale and female MitoQC mice aged 24 months received either standard chow or chow supplemented with BAM15 (0.033% mg/g) ad libitum for eight weeks (n=13-14/group). Young (3-month-old) mice served as reference controls (n=8/group). Muscle mitochondrial respiration was assessed in permeabilized fib res, and contractile function was measured in isolated extensor digitorum longus and soleus muscles. Mitophagy was quantified by immunofluorescence confocal microscopy. Data were analyzed using one-or two-way ANOVA followed by Dunnetts or Bonferronis multiple comparison tests. ResultsAged male and female mice exhibited reduced gastrocnemius muscle mass relative to body mass compared with young controls (p<0.05; [~]18% and [~]32% loss, respectively). BAM15 did not alter muscle size but reversed the age-related loss of contractile function in EDL muscles, to that of the young reference controls in both sexes (p<0.05; [~]33% in males, [~]16% in females). In male mice, BAM15 improved mitochondrial efficiency, evidenced by restoration of Complex I-linked respiration and decreased proton leak ([~]52% improvement; p<0.05), and normalized protein levels of oxidative stress marker 4 -HNE, without changes in mitophagy or mitochondrial content. In females, BAM15 did not improve mitochondrial parameters, which may be, in part, due to aged female muscle exhibiting unchanged Complex I leak and 4-HNE protein abundance, alongside lower complex I subunit (NDUFB8) protein abundance. ConclusionsBAM15 improved skeletal muscle mitochondrial efficiency and contractile function in aged male mice, supporting the potential of mitochondrial uncoupling as a therapeutic strategy for sarcopenia.

physiology↗

bioRxiv2025

Anabolic and catabolic responses to different modes of exercise in patients with chronic kidney disease

BackgroundMuscle wasting is a common complication in individuals with chronic kidney disease (CKD) and contributes to reduced physical function and poor clinical outcomes. While exercise is recommended for CKD patients, the molecular responses to different exercise modalities remain poorly understood. This study aimed to investigate the anabolic, catabolic, and myogenic responses of skeletal muscle to aerobic exercise (AE) and combined exercise (CE; aerobic plus resistance) in people with CKD. MethodsMuscle biopsies were collected from participants in a 12-week randomized controlled trial of supervised exercise training, the ExTRA CKD trial. Samples were obtained at baseline, 24 hours after an initial bout of exercise (untrained), and 24 hours after the final training session (trained). Western blotting and RT-qPCR were used to assess changes in key markers of protein synthesis, degradation, and regeneration. To complement these data, in vitro experiments using mechanically stretched primary skeletal muscle cells from CKD and healthy control donors were used to explore the time course of anabolic signalling. ResultsIn vivo, Akt phosphorylation was blunted following unaccustomed CE but significantly upregulated following training, indicating partial restoration of anabolic signalling. No change was observed in response to AE. Myostatin expression was significantly downregulated following both AE and CE in the untrained state, while Pax7 and myogenic gene expression were upregulated only in response to CE after training. In vitro, mechanical stretch induced significant phosphorylation of Akt and p70S6K in both CKD and control cells, with no group difference in Akt response and a trend toward faster return to baseline of p70S6K phosphorylation in CKD cells. ConclusionThese findings demonstrate that CE, but not AE, induces beneficial anabolic and myogenic responses in skeletal muscle in CKD, and highlight the value of combining in vivo and in vitro models to explore temporal dynamics and mechanistic insight into muscle adaptation. What was knownO_LIPeople with CKD often have impaired skeletal muscle responses to exercise, termed anabolic resistance, which may contribute to muscle wasting and poor outcomes. C_LIO_LIResistance exercise activates anabolic and myogenic pathways in healthy muscle, but the extent of these responses in CKD is unclear. C_LIO_LILimited studies have compared molecular responses to different exercise modalities in CKD, particularly combining in vivo and in vitro approaches. C_LI This study addsO_LICombined aerobic-resistance exercise, but not aerobic exercise alone, restored aspects of anabolic signalling (Akt phosphorylation) in CKD skeletal muscle after training. C_LIO_LIMyogenic gene expression was upregulated following combined exercise but not aerobic exercise, indicating a modality-specific regenerative response. C_LIO_LIIn vitro, primary muscle cells from CKD and healthy donors showed similar early anabolic responses to mechanical stretch, though CKD cells may return to baseline more rapidly. C_LI Potential ImpactO_LISupports inclusion of resistance-based modalities in exercise prescriptions for people with CKD to enhance muscle anabolic and regenerative responses. C_LIO_LISuggests that exercise prescriptions for CKD should prioritise combined modalities to maximise muscle anabolic and regenerative potential. C_LIO_LIProvides mechanistic evidence to inform tailored exercise interventions aimed at preserving muscle health in CKD patients. C_LI

molecular biology↗

bioRxiv2024

Anabolic sensitivity in healthy, lean, older men is associated with higher expression of amino acid sensors and mTORC1 activators

BackgroundSarcopenia is thought to be underlined by age-associated anabolic resistance and dysregulation of intracellular signalling pathways. However, it is unclear whether these phenomena are driven by ageing per se or other confounding factors. MethodsLean and healthy young (n=10, 22 {+/-} 3 yrs, BMI; 23.4 {+/-} 0.8 kg/m2) and old men (n=10, 70 {+/-} 3 yrs, BMI; 22.7 {+/-} 1.3 kg/m2) performed unilateral resistance exercise followed by intake of essential amino acids (EAA). Muscle biopsies were collected from the rested and the exercised leg before, immediately after, as well as 60 and 180 minutes after EAA intake. Muscle samples were analyzed for amino acid concentrations, muscle protein synthesis (MPS) and associated anabolic signaling. ResultsFollowing exercise, peak plasma levels of EAA and leucine were similar between groups, but the area under the curve was [~]11% and [~]28% lower in Young (p<0.01). Absolute levels of muscle EAA and leucine peaked 60 min after exercise, with [~]15 and [~]21 % higher concentrations in the exercising leg (p<0.01) but with no difference between groups. MPS increased in both the resting ([~] 0.035%{middle dot}h-1 to 0.056%{middle dot}h-1, p<0.05) and exercising leg ([~] 0.035%{middle dot}h-1 to 0.083%{middle dot}h-1, p<0.05) with no difference between groups. Phosphorylation of S6K1Thr389 increased to a similar extent in the exercising leg in both groups but was 2.8-fold higher in the resting leg of Old at the 60 min timepoint (p<0.001). Phosphorylation of 4E-BP1Ser65 increased following EAA intake and exercise, but differences between legs were statistically different only at 180 min (p<0.001). However, phosphorylation of this site was on average 78% greater across all timepoints in Old (p<0.01). Phosphorylation of eEF2Thr56 was reduced ([~] 66 and 39%) in the exercising leg at both timepoints after EAA intake and exercise, with no group differences (p<0.05). However, phosphorylation at this site was reduced by [~] 27% also in the resting leg at 60 min, an effect that was only seen in Old (p<0.01). Total levels of Rheb ([~] 45%), LAT1 ([~] 31%) and Rag B ([~] 31%) were higher in Old (p<0.001). ConclusionLean and healthy old men do not manifest AR as evidenced by potent increases in MPS and mTORC1 signalling following EAA intake and exercise. Maintained anabolic sensitivity with age appears to be a function of a compensatory increase in basal levels of proteins involved in anabolic signalling. Therefore, our results suggest that age per se does not appear to cause AR in human skeletal muscle.

physiology↗

bioRxiv2022

Decreased miRNA-148a-3p expression in skeletal muscle of patients with chronic kidney disease

IntroductionSkeletal muscle wasting is a common complication of chronic kidney disease which leads to a loss of muscle function. The pathogenesis of skeletal muscle wasting is incompletely understood, which is preventing the development of targeted therapeutics. Recent evidence implicates miRNAs in the of skeletal muscle wasting. Our aim was to firstly examine miRNA profiles of CKD human skeletal muscle for the identification of aberrant expression patterns compared to a healthy control (HC) cohort, and secondly, investigate the role these miRNAs may play in inducing or promoting skeletal muscle atrophy using a novel human primary skeletal muscle cell model of CKD skeletal muscle. MethodsFor the comparison between CKD and HC populations, skeletal muscle biopsies were collected from the vastus lateralis of n=15 non-dialysis dependent CKD patients stage 3b-5 CKD patients, and n=15 healthy controls matched for age, gender and physical activity. n=5 biopsies from each group underwent next generation sequencing to obtain complete microRNA profiles in CKD vs HC cohorts, which were then validated in a separate cohort by PCR (N=10 in each group). A causative role in muscle wasting was determined by transfection of key microRNAs into a primary culture model of CKD skeletal muscle and changes in protein degradation determined by L-[3H]- phenylalanine release into the media. ResultsNext Generation Sequencing identified differential expression of 16 miRNAs in skeletal muscle of CKD patients versus controls, and PCR validation confirmed miRNA-148a-3p expression was significantly decreased in CKD patients. The reduced miRNA-148a-3p expression was also maintained in the primary culture model. Upon overexpression of miRNA-148a-3p in CKD myotubes, protein degradation rates were decreased non-significantly (p=0.28) by 16.3% compared to un-transfected CKD cells. ConclusionCKD was associated with a significant reduction in miRNA-148a-3p expression in skeletal muscle compared to non-CKD controls which was retained in our in vitro model. Overexpression of miRNA-148a-3p in primary skeletal myotubes non-significantly decreased muscle protein degradation by 16.3%. In order to determine the importance of miRNA-148a-regulation of protein degradation, a deeper understanding of miRNA-148a-3p targets and their associated pathways with respect to those dysregulated in skeletal muscle wasting is required.

molecular biology↗

bioRxiv2020

Establishment and characterisation of primary skeletal muscle cell cultures from patients with advanced Chronic Kidney Disease

Skeletal muscle wasting and dysfunction is a common characteristic of non-dialysis dependent chronic kidney disease (NDD-CKD). The mechanisms by which this occurs are not clearly understood and one reason for this is a lack of well controlled in-vitro methodologies to simulate NDD-CKD induced muscle wasting for mechanistic investigation at the cellular level. Here we sought to conduct the initial investigations into developing a CKD-induced skeletal muscle model for use as a mechanistic analysis tool as well as a test bed for potential novel therapeutics in this population. Human derived muscle cells (HDMCs) were isolated from n=5 NDD-CKD patients and n=3 matched healthy controls (HC) and taken through proliferation and differentiation phases in cell culture. Upon comparison of the 2 donor types, significantly greater mRNA expression of myogenic markers was noted in the NDD-CKD cultures in comparison to HC cultures, which was carried through to greater mRNA expression of myosin heavy chains (MyHCs) post differentiation. However, this was not carried over to protein expression where Pax7 and MyoD were seen to be expressed to a greater extent in HC cultures. mRNA expression markers of protein degradation were noted to be elevated in NDD-CKD cultures in comparison to HC cultures. In light of our findings, future work should seek to investigate the role of the CKD environment as well as mechanisms implicated in transcription regulation to further advance the current model development as well as the mechanistic understanding of skeletal muscle wasting in CKD.

cell biology↗

bioRxiv2020

Association between vitamin D deficiency and exercise capacity in patients with CKD, a cross-sectional analysis

Evidence is growing for a role of vitamin D in regulating skeletal muscle mass, strength and functional capacity. Given the role the kidneys play in activating total vitamin D, and the high prevalence of vitamin D deficiency in Chronic Kidney Disease (CKD), it is possible that deficiency contributes to the low levels of physical function and muscle mass in these patients. This is a secondary cross-sectional analysis of previously published interventional study, with ex vivo follow up work. 34 CKD patients at stages G3b-5 (eGFR 25.5 {+/-} 8.3ml/min/1.73m2; age 61 {+/-} 12 years) were recruited, with a sub-group (n=20) also donating a muscle biopsy. Vitamin D and associated metabolites were analysed in plasma by liquid chromatography tandem-mass spectroscopy and correlated to a range of physiological tests of muscle size, function, exercise capacity and body composition. The effects of 1,25(OH)2D3 supplementation on myogenesis and myotube size was investigated in primary skeletal muscle cells from vitamin D deficient donors. In vivo, there was no association between total or active vitamin D and muscle size or strength, but a significant correlation with [Formula] was seen with the total form. Ex vivo, 1,25(OH)2D3 supplementation reduced IL-6 mRNA expression, but had no effect upon proliferation, differentiation or myotube diameter. This early preliminary work suggests that vitamin D deficiency is not a prominent factor driving the loss of muscle mass in CKD, but may play a role in reduced exercise capacity.

cell biology↗

bioRxiv2020

Nicotinamide Riboside supplementation does not alter whole-body or skeletal muscle metabolic responses to a single bout of endurance exercise

Oral supplementation of the NAD+ precursor Nicotinamide Riboside (NR) has been reported to increase Sirtuin (SIRT) signalling, mitochondrial biogenesis and endurance capacity in rodent skeletal muscle. However, whether NR supplementation can elicit a similar response in human skeletal muscle is unclear. This study aimed to assess the effect of 7-day NR supplementation on exercise-induced transduction and transcriptional responses in skeletal muscle of young, healthy, recreationally active human volunteers. In a double-blinded, randomised, counter-balanced, crossover design, eight male participants (age: 23 ± 4 years, VO2peak: 46.5 ± 4.4 mL·kg-1·min-1) received one week of NR or cellulose placebo (PLA) supplementation (1000 mg·d-1) before performing one hour of cycling at 60% Wmax. Muscle biopsies were collected prior to supplementation and pre-, immediately and three-hours post-exercise from the medial vastus lateralis, whilst venous blood samples were collected throughout the trial. Global acetylation, auto-PARylation of PARP1, acetylation of p53Lys382 and MnSODLys122 were unaffected by NR supplementation or exercise. Exercise led to an increase in AMPKThr172 (1.6-fold), and ACCSer79 (4-fold) phosphorylation, in addition to an increase in PGC-1α (∼5-fold) and PDK4 (∼10-fold) mRNA expression, however NR had no additional effect on this response. There was also no effect of NR supplementation on substrate utilisation at rest or during exercise or on skeletal muscle mitochondrial respiration. Finally, NR supplementation blunted the exercise induced activation of skeletal muscle NNMT mRNA expression, but had no effect on mRNA expression of NMRK1, NAMPT or NMNAT1, which were not significantly affected by NR supplementation or exercise. In summary, one week of NR supplementation does not augment skeletal muscle signal transduction pathways implicated in mitochondrial adaptation to endurance exercise.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2020

Diet-Induced Vitamin D Deficiency Results in Reduced Skeletal Muscle Mitochondrial Respiration in C57BL/6J Mice

Vitamin D deficiency is known to be associated with symptoms of skeletal muscle myopathy including muscle weakness and fatigue. Recently, vitamin D related metabolites have been linked to the maintenance of mitochondrial function within skeletal muscle. However, current evidence is limited to in vitro models and the effects of diet-induced vitamin D deficiency upon skeletal muscle mitochondrial function in vivo have received little attention. In order to examine the role of vitamin D in the maintenance of mitochondrial function in vivo, we utilised an established model of diet-induced vitamin D deficiency in C57BL/6J mice. Mice were fed either a control (2,200 IU/kg) or a vitamin D deplete (0 IU/kg) diet for periods of 1-, 2- and 3-months. Skeletal muscle mitochondrial function and ADP sensitivity were assessed via high-resolution respirometry and mitochondrial protein content via immunoblotting. As a result of 3-month of diet-induced vitamin D deficiency, respiration supported via CI+IIP and ETC were 35% and 37% lower when compared to vitamin D replete mice (P < 0.05). Despite functional alterations, the protein expression of electron transfer chain subunits remained unchanged in response to dietary intervention (P > 0.05). In conclusion, we report that 3-months of diet-induced vitamin D deficiency reduced skeletal muscle mitochondrial function in C57BL/6J mice. Our data, when combined with previous in vitro observations, suggests that vitamin D mediated regulation of mitochondrial function may underlie the exacerbated muscle fatigue and performance deficits observed during vitamin D deficiency.

physiology↗

bioRxiv2020

Protein-carbohydrate ingestion alters Vps34 cellular localization independent of changes in kinase activity in human skeletal muscle

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell size and growth in response to nutrients, however, the mechanisms by which nutrient levels are sensed by mTORC1 in human skeletal muscle are yet to be fully elucidated. The Class III PI3Kinase Vps34 has recently been proposed as a sensor essential for mTORC1 activation following nutrient stimulation. We therefore investigated the effects of increasing nutrient availability through protein-carbohydrate (PRO-CHO) feeding on Vps34 kinase activity and cellular localization in human skeletal muscle. Eight young, healthy males (age - 21 {+/-} 0.5yrs, mean {+/-} SEM) ingested a PRO-CHO beverage containing 20/44/1g PRO/CHO/FAT respectively, with skeletal muscle biopsies obtained at baseline and 1h and 3h post-feeding. PRO-CHO feeding did not alter Vps34 kinase activity, but did stimulate Vps34 translocation toward the cell periphery (PRE (mean{+/-}SEM) - 0.273{+/-}0.021, 1h - 0.347{+/-}0.022, Pearsons Coefficient (r)) where it co-localized with mTOR (PRE - 0.312{+/-}0.018, 1h - 0.348{+/-}0.024, Pearsons Coefficient (r))). These alterations occurred in parallel to an increase in S6K1 kinase activity - 941{+/-}164% of PRE at 1h post-feeding). Subsequent in vitro experiments in C2C12 and human primary myotubes displayed no effect of the Vps34-specific inhibitor SAR405 on mTORC1 signalling responses to elevated nutrient availability. Therefore, in summary, PRO-CHO ingestion does not increase Vps34 activity in human skeletal muscle, whilst pharmacological inhibition of Vps34 does not prevent nutrient stimulation of mTORC1 in vitro. However, PRO-CHO ingestion promotes Vps34 translocation to the cell periphery, enabling Vps34 to associate with mTOR. Therefore, our data suggests that interaction between Vps34 and mTOR, rather than changes in Vps34 activity per se may be involved in PRO-CHO activation of mTORC1 in human skeletal muscle.

physiology↗

bioRxiv2019

The Vitamin D Receptor (VDR) Regulates Mitochondrial Function in C2C12 Myoblasts

Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity, however, the mechanistic basis of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to the vitamin D receptor (VDR). Recent evidence has linked 1,25(OH)2D3 to the regulation of skeletal muscle mitochondrial function in vitro, however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we utilised lentiviral mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared to shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes (P < 0.001). VDR-KD myoblasts displayed a 30%, 30% and 36% reduction in basal, coupled and maximal respiration respectively (P < 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33% and 48% reduction in basal, coupled and maximal respiration (P < 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATPox) was reduced by 20% suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content as well as markers of fusion and fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro, providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.

physiology↗

bioRxiv2019

Lipid metabolism links nutrient-exercise timing to insulin sensitivity in men classified as overweight or obese.

ContextPre-exercise nutrient availability alters acute metabolic responses to exercise, which could modulate training responsiveness. We hypothesised that in men with overweight/obesity, acute exercise before versus after nutrient ingestion would increase whole-body and intramuscular lipid utilization, translating into greater increases in oral glucose insulin sensitivity over 6-weeks of training.\n\nDesign and ParticipantsWe showed in men with overweight/obesity (mean{+/-}SD for BMI: 30.2{+/-}3.5 kgxm-2 for acute, crossover study, 30.9{+/-}4.5 kgxm-2 for randomized, controlled, training study) a single exercise bout before versus after nutrient provision increased lipid utilisation at the whole-body level, but also in both type I (p<0.01) and type II muscle fibres (p=0.02). We then used a 6-week training intervention to show sustained, 2-fold increases in lipid utilisation with exercise before versus after nutrient provision (p<0.01).\n\nMain Outcome MeasuresPostprandial glycemia was not differentially affected by exercise training before vs after nutrient provision (p>0.05), yet plasma was reduced with exercise training before, but not after nutrient provision (p=0.03), resulting in increased oral glucose insulin sensitivity when training was performed before versus after nutrient provision (25{+/-}38 vs -21{+/-}32 mLxmin-1xm-2; p=0.01) and this was associated with increased lipid utilisation during exercise (r=0.50, p=0.02). Regular exercise prior to nutrient provision augmented remodelling of skeletal muscle phospholipids and protein content of the glucose transport protein GLUT4 (p<0.05).\n\nConclusionsExperiments investigating exercise training and metabolic health should consider nutrient-exercise timing, and exercise performed before versus after nutrient intake (i.e., in the fasted state) may exert beneficial effects on lipid utilisation and reduce postprandial insulinemia.\n\nPrecisExercise in the fasted-versus fed-state increased intramuscular and whole-body lipid use, translating into increased muscle adaptation and insulin sensitivity when regularly performed over 6 weeks.

physiology↗

bioRxiv2019

Nicotinamide riboside augments the human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures in aged subjects: a placebo-controlled, randomized trial

NAD+ is modulated by conditions of metabolic stress and has been reported to decline with aging, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome, and questioned if tissue NAD+ levels are depressed with aging. We supplemented 12 aged men with NR 1g per day for 21-days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways. NR also depressed levels of circulating inflammatory cytokines. In an additional study, 31P magnetic resonance spectroscopy-based NAD+ measurement in muscle and brain showed no difference between young and aged individuals. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR, while suggesting that NAD+ decline is not associated with chronological aging per se in human muscle or brain.

clinical trials↗