Dietary fat oxidation is elevated in middle-aged type 2 diabetes

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Transient transcriptional events in human skeletal muscle at the outset of concentric resistance exercise training

We sought to ascertain the time course of transcriptional events that occur in human skeletal muscle at the outset of resistance exercise (RE) training in RE naive individuals and determine whether the magnitude of response was associated with exercise-induced muscle damage. Sixteen RE naive men were recruited; eight underwent two sessions of 5 × 30 maximum isokinetic knee extensions (180°/s) separated by 48 h. Muscle biopsies of the vastus lateralis, obtained from different sites, were taken at baseline and 24 h after each exercise bout. Eight individuals acted as nonexercise controls with biopsies obtained at the same time intervals. Transcriptional changes were assessed by microarray and protein levels of heat shock protein (HSP) 27 and αB-crystallin in muscle cross sections by immunohistochemistry as a proxy measure of muscle damage. In control subjects, no probe sets were significantly altered (false discovery rate < 0.05), and HSP27 and αB-crystallin protein remained unchanged throughout the study. In exercised subjects, significant intersubject variability following the initial RE bout was observed in the muscle transcriptome, with greatest changes occurring in subjects with elevated HSP27 and αB-crystallin protein. Following the second bout, the transcriptome response was more consistent, revealing a cohort of probe sets associated with immune activation, the suppression of oxidative metabolism, and ubiquitination, as differentially regulated. The results reveal that the initial transcriptional response to RE is variable in RE naive volunteers, potentially associated with muscle damage and unlikely to reflect longer term adaptations to RE training. These results highlight the importance of considering multiple time points when determining the transcriptional response to RE and associated physiological adaptation

Human skeletal muscle is refractory to the anabolic effects of leucine during the postprandial muscle-full period in older men

Leucine modulates muscle protein synthesis (MPS), with potential to facilitate accrual/maintenance of muscle mass. Animal models suggest that leucine boluses shortly after meals may prolong MPS and delay onset of a “muscle-full” state. However, the effects of nutrient “top-ups” in humans, and particularly older adults where deficits exist, have not been explored. We determined the effects of a leucine top-up after essential amino acid (EAA) feeding on anabolic signaling, MPS, and muscle energy metabolism in older men. During 13C6-phenylalanine infusion, 16 men (∼70 years) consumed 15 g of EAA with (n=8, FED + LEU) or without (n=8, FED) 3 g of leucine top-up 90 min later. Repeated blood and muscle sampling permitted measurement of fasting and postprandial plasma EAA, insulin, anabolic signaling including mTOR complex 1 (mTORC1) substrates, cellular ATP and phosphorylocreatine, and MPS. Oral EAA achieved rapid insulinemia (12.5 iU·ml−1 25 min post-feed), essential aminoacidemia (3000 μM, 45–65 min post-feed), and activation of mTORC1 signaling. Leucine top-up prolonged plasma EAA (2800 μM, 135 min) and leucine availability (1050 μM, 135 min post-feed). Fasting FSRs of 0.046 and 0.056%·h-1 (FED and FED + LEU respectively) increased to 0.085 and 0.085%·h-1 90–180 min post-feed and returned to basal rates after 180 min in both groups. Phosphorylation of mTORC1 substrates returned to fasting levels 240 min post-feed in both groups. Feeding had limited effect on muscle elongation factor 2 (eEF2) phosphorylation. We demonstrate the refractoriness of muscle to nutrient-led anabolic stimulation in the postprandial period; thus, leucine supplements should be taken outside of meals, or with meals containing suboptimal protein in terms of either amount or EAA composition

Age-related changes in muscle architecture and metabolism in humans: The likely contribution of physical inactivity to age-related functional decline

In the United Kingdom (UK), it is projected that by 2035 people aged >65 years will make up 23 % of the population, with those aged >85 years accounting for 5% of the total population. Ageing is associated with progressive changes in muscle metabolism and a decline in functional capacity, leading to a loss of independence. Muscle metabolic changes associated with ageing have been linked to alterations in muscle architecture and declines in muscle mass and insulin sensitivity. However, the biological features often attributed to muscle ageing are also seen in controlled studies of physical inactivity (e.g. reduced step-count and bed-rest), and it is currently unclear how many of these ageing features are due to ageing per se or sedentarism. This is particularly relevant at a time of home confinements reducing physical activity levels during the Covid-19 pandemic. Current knowledge gaps include the relative contribution that physical inactivity plays in the development of many of the negative features associated with muscle decline in older age. Similarly, data demonstrating positive effects of government recommended physical activity guidelines on muscle health are largely non-existent. It is imperative therefore that research examining interactions between ageing, physical activity and muscle mass and metabolic health is prioritised so that it can inform on the “normal” muscle ageing process and on strategies for improving health span and well-being. This review will focus on important changes in muscle architecture and metabolism that accompany ageing and highlight the likely contribution of physical inactivity to these changes

Associations between plasma branched chain amino acids and health biomarkers in response to resistance exercise training across age

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Leucine, isoleucine and valine (i.e., the branched chain amino acids, BCAA) play a key role in the support and regulation of tissue protein regulation and also as energy substrates. However, positive relationships exist between elevated levels of BCAA and insulin resistance (IR). Thus, we sought to investigate the links between fasting plasma BCAA following a progressive resistance exercise training (RET) programme, an intervention known to improve metabolic health. Fasting plasma BCAA were quantified in adults (young: 18–28 y, n = 8; middle-aged: 45–55 y, n = 9; older: 65–75 y, n = 15; BMI: 23–28 kg/m2, both males and females (~50:50), in a cross-sectional, intervention study. Participants underwent 20-weeks whole-body RET. Measurements of body composition, muscle strength (1-RM) and metabolic health biomarkers (e.g., HOMA-IR) were made pre-and post-RET. BCAA concentrations were determined by gas-chromatography mass spectrometry (GC-MS). No associations were observed across age with BCAA; however, RET elicited (p < 0.05) increases in plasma BCAA (all age-groups), while HOMA-IR scores reduced (p < 0.05) following RET. After RET, positive correlations in lean body mass (p = 0.007) and strength gains (p = 0.001) with fasting BCAA levels were observed. Elevated BCAA are not a robust marker of ageing nor IR in those with a healthy BMI; rather, despite decreasing IR, RET was associated with increased BCAA

Caloric restriction improves glycaemic control without reducing plasma branched-chain amino acids or keto-acids in obese men

Higher plasma leucine, isoleucine and valine (BCAA) concentrations are associated with diabetes, obesity and insulin resistance (IR). Here, we evaluated the effects of 6-weeks very-low calorie diet (VLCD) upon fasting BCAA in overweight (OW) non-diabetic men, to explore associations between circulating BCAA and IR, before and after a weight loss intervention. Fasting plasma BCAAs were quantified in an OW (n = 26; BMI 32.4 ± 3 kg/m2; mean age 44 ± 9 y) and a normal-weight (NW) group (n = 26; BMI 24 ± 3.1 kg/m2; mean age 32 ± 12.3 y). Ten of the OW group (BMI 32.2 ± 4 kg/m2; 46 ± 8 y) then underwent 6-weeks of VLCD (600–800 kcal/day). Fasting plasma BCAA (gas chromatography-mass spectrometry), insulin sensitivity (HOMA-IR) and body-composition (DXA) were assessed before and after VLCD. Total BCAA were higher in OW individuals (sum leucine/isoleucine/valine: 457 ± 85 µM) compared to NW control individuals (365 ± 78 µM, p < 0.001). Despite significant weight loss (baseline 103.9 ± 12.3 to 93 ± 9.6 kg and BMI 32.2 ± 4 to 28.9 ± 3.6 kg/m2), no changes were observed in BCAAs after 6-weeks of VLCD. Moreover, although VLCD resulted in a significant reduction in HOMA-IR (baseline 1.19 ± 0.62 to 0.51 ± 0.21 post-VLCD; p < 0.001), Pearson’s r revealed no relationships between BCAA and HOMA-IR, either before (leucine R2: 2.49e−005, p = 0.98; isoleucine R2: 1.211−e006, p = 0.9; valine R2: 0.004, p = 0.85) or after VLCD (leucine R2: 0.003, p = 0.86; isoleucine R2: 0.006, p = 0.82; valine R2: 0.002, p = 0.65). Plasma BCAA are higher in OW compared to NW individuals. However, while 6-weeks VLCD reduced body weight and IR in OW individuals, this was not associated with reductions in BCAA. This suggests that studies demonstrating links between BCAA and insulin resistance in OW individuals, are complex and are not normalised by simply losing weight

Analysis of the efficacy, safety, and regulatory status of novel forms of creatine

Creatine has become one of the most popular dietary supplements in the sports nutrition market. The form of creatine that has been most extensively studied and commonly used in dietary supplements is creatine monohydrate (CM). Studies have consistently indicated that CM supplementation increases muscle creatine and phosphocreatine concentrations by approximately 15–40%, enhances anaerobic exercise capacity, and increases training volume leading to greater gains in strength, power, and muscle mass. A number of potential therapeutic benefits have also been suggested in various clinical populations. Studies have indicated that CM is not degraded during normal digestion and that nearly 99% of orally ingested CM is either taken up by muscle or excreted in urine. Further, no medically significant side effects have been reported in literature. Nevertheless, supplement manufacturers have continually introduced newer forms of creatine into the marketplace. These newer forms have been purported to have better physical and chemical properties, bioavailability, efficacy, and/or safety profiles than CM. However, there is little to no evidence that any of the newer forms of creatine are more effective and/or safer than CM whether ingested alone and/or in combination with other nutrients. In addition, whereas the safety, efficacy, and regulatory status of CM is clearly defined in almost all global markets; the safety, efficacy, and regulatory status of other forms of creatine present in today’s marketplace as a dietary or food supplement is less clear

Creatine ingestion augments dietary carbohydrate mediated muscle glycogen supercomposition during the initial 24 hrs of recovery following prolonged exhaustive exercise in humans

Muscle glycogen availability can limit endurance exercise performance. We previously demonstrated 5 days of creatine (Cr) and carbohydrate (CHO) ingestion augmented post-exercise muscle glycogen storage compared to CHO feeding alone in healthy volunteers. Here we aimed to characterise the time-course of this Cr-induced response under more stringent and controlled experimental conditions and identify potential mechanisms underpinning this phenomenon. Fourteen healthy, male volunteers cycled to exhaustion at 70% VO2peak. Muscle biopsies were obtained at rest immediately post-exercise and after 1, 3 and 6 days of recovery, during which Cr or placebo supplements (20g.day-1) were ingested along with a prescribed high CHO diet (37.5 kcal.kg body mass-1.day-1, >80% calories CHO). Oral-glucose tolerance tests (oral-GTT) were performed pre-exercise and after 1, 3 and 6 days of Cr and placebo supplementation. Exercise depleted muscle glycogen content to the same extent in both treatment groups. Creatine supplementation increased muscle total-Cr, free-Cr and phosphocreatine (PCr) content above placebo following 1, 3 and 6 days of supplementation (all P<0.05). Creatine supplementation also increased muscle glycogen content noticeably above placebo after 1 day of supplementation (P<0.05), which was sustained thereafter. This study confirmed dietary Cr augments post-exercise muscle glycogen super-compensation, and demonstrates this occurred during the initial 24 h of post-exercise recovery (when muscle total-Cr had increased by <10%). This marked response ensued without apparent treatment differences in muscle insulin sensitivity (oral-GTT, muscle GLUT4 mRNA), osmotic stress (muscle c-fos and HSP72 mRNA) or muscle cell volume (muscle water content) responses, such that another mechanism must be causative

Effects of leucine-enriched essential amino acid and whey protein bolus dosing upon skeletal muscle protein synthesis at rest and after exercise in older women

Background & aims: Impaired anabolic responses to nutrition and exercise contribute to loss of skeletal muscle mass with ageing (sarcopenia). Here, we tested responses of muscle protein synthesis (MPS), in the under represented group of older women, to leucine-enriched essential amino acids (EAA) in comparison to a large bolus of whey protein (WP). Methods: Twenty-four older women (65 ± 1 y) received (N ¼ 8/group) 1.5 g leucine-enriched EAA supplements (LEAA_1.5), 6 g LEAA (LEAA_6) in comparison to 40 g WP. A primed constant I.V infusion of 13C6-phenylalanine was used to determine MPS at baseline and in response to feeding (FED) and feeding-plus-exercise (FED-EX; 6 x 8 unilateral leg extensions; 75%1-RM). We quantified plasma insulin/AA concentrations, leg femoral blood flow (LBF)/muscle microvascular blood flow (MBF), and anabolic signalling via immunoblotting. Results: Plasma insulineamia and EAAemia were greater and more prolonged with WP than LEAA, although LEAA_6 peaked at similar levels to WP. Neither LEAA or WP modified LBF or MBF. FED increased MPS similarly in the LEAA_1.5, LEAA_6 and WP (P < 0.05) groups over 0e2 h, with MPS significantly higher than basal in the LEAA_6 and WP groups only over 0e4 h. However, FED-EX increased MPS similarly across all the groups from 0 to 4 h (P < 0.05). Only p-p70S6K1 increased with WP at 2 h in FED (P < 0.05), and at 2/4 h in FED-EX (P < 0.05). Conclusions: In conclusion, LEAA_1.5, despite only providing 0.6 g of leucine, robustly (perhaps maximally) stimulated MPS, with negligible trophic advantage of greater doses of LEAA or even to 40 g WP. Highlighting that composition of EAA, in particular the presence of leucine rather than amount is most crucial for anabolism

Untargeted metabolomics for uncovering biological markers of human skeletal muscle ageing

Ageing compromises skeletal muscle mass and function through poorly defined molecular aetiology. Here we have used untargeted metabolomics using UHPLC-MS to profile muscle tissue from young (n=10, 25±4y), middle aged (n=18, 50±4y) and older (n=18, 70±3y) men and women (50:50). Random Forest was used to prioritise metabolite features most informative in stratifying older age, with potential biological context examined using the prize-collecting Steiner forest algorithm embedded in the PIUMet software, to identify metabolic pathways likely perturbed in ageing. This approach was able to filter a large dataset of several thousand metabolites down to subnetworks of age important metabolites. Identified networks included the common age-associated metabolites such as androgens, (poly)amines/amino acids and lipid metabolites, in addition to some potentially novel ageing related markers such as dihydrothymine and imidazolone-5-proprionic acid. The present study reveals that this approach is a potentially useful tool to identify processes underlying human tissue ageing, and could therefore be utilised in future studies to investigate the links between age predictive metabolites and common biomarkers linked to health and disease across age