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Key points: Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion increases muscle microvascular blood flow which in part facilitates glucose delivery and disposal. In contrast, high‐glucose ingestion impairs muscle microvascular blood flow which may contribute to impaired postprandial metabolism.We investigated the effects of prior cycling exercise on postprandial muscle microvascular blood flow responses to a high‐glucose mixed‐nutrient meal ingested 3 and 24 h post‐exercise.Prior exercise enhanced muscle microvascular blood flow and mitigated microvascular impairments induced by a high‐glucose mixed meal ingested 3 h post‐exercise, and to a lesser extent 24 h post‐exercise.High‐glucose ingestion 3 h post‐exercise leads to greater postprandial blood glucose, non‐esterified fatty acids, and fat oxidation, and a delay in the insulin response to the meal compared to control.Effects of acute exercise on muscle microvascular blood flow persist well after the cessation of exercise which may be beneficial for conditions characterized by microvascular and glycaemic dysfunction. Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion lead to increased muscle microvascular blood flow (MBF), whereas high‐glucose ingestion impairs MBF. We investigated whether prior cycling exercise could enhance postprandial muscle MBF and prevent MBF impairments induced by high‐glucose mixed‐nutrient meal ingestion. In a randomized cross‐over design, eight healthy young men ingested a high‐glucose mixed‐nutrient meal (1.1 g glucose/kg body weight; 45% carbohydrate, 20% protein and 35% fat) after an overnight fast (no‐exercise control) and 3 h and 24 h after moderate‐intensity cycling exercise (1 h at 70–75% V̇O2peak). Skeletal muscle MBF, measured directly by contrast‐enhanced ultrasound, was lower at 60 min and 120 min postprandially compared to baseline in all conditions (P < 0.05), with a greater decrease occurring from 60 min to 120 min in the control (no‐exercise) condition only (P < 0.001). Despite this meal‐induced decrease, MBF was still markedly higher compared to control in the 3 h post‐exercise condition at 0 min (pre‐meal; 74%, P = 0.004), 60 min (112%, P = 0.002) and 120 min (223%, P < 0.001), and in the 24 h post‐exercise condition at 120 min postprandially (132%, P < 0.001). We also report that in the 3 h post‐exercise condition postprandial blood glucose, non‐esterified fatty acids (NEFAs), and fat oxidation were substantially elevated, and the insulin response to the meal delayed compared to control. This probably reflects a combination of increased post‐exercise exogenous glucose appearance, substrate competition, and NEFA‐induced insulin resistance. We conclude that prior cycling exercise elicits long‐lasting effects on muscle MBF and partially mitigates MBF impairments induced by high‐glucose mixed‐nutrient meal ingestion. Key points: Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion increases muscle microvascular blood flow which in part facilitates glucose delivery and disposal. In contrast, high‐glucose ingestion impairs muscle microvascular blood flow which may contribute to impaired postprandial metabolism.We investigated the effects of prior cycling exercise on postprandial muscle microvascular blood flow responses to a high‐glucose mixed‐nutrient meal ingested 3 and 24 h post‐exercise.Prior exercise enhanced muscle microvascular blood flow and mitigated microvascular impairments induced by a high‐glucose mixed meal ingested 3 h post‐exercise, and to a lesser extent 24 h post‐exercise.High‐glucose ingestion 3 h post‐exercise leads to greater postprandial blood glucose, non‐esterified fatty acids, and fat oxidation, and a delay in the insulin response to the meal compared to control.Effects of acute exercise on muscle microvascular blood flow persist well after the cessation of exercise which may be beneficial for conditions characterized by microvascular and glycaemic dysfunction. [ABSTRACT FROM AUTHOR]

There is evidence that increasing carbohydrate (CHO) availability during exercise by raising preexercise muscle glycogen levels attenuates the activation of AMPK[alpha]2 during exercise in humans. Similarly, increasing glucose levels decreases AMPK[alpha]2 activity in rat skeletal muscle in vitro. We examined the effect of CHO ingestion on skeletal muscle AMPK signaling during exercise in nine active male subjects who completed two 120-min bouts of cycling exercise at 65 [+ or -] 1% go2 peak. In a randomized, counterbalanced order, subjects ingested either an 8% CHO solution or a placebo solution during exercise. Compared with the placebo trial, CHO ingestion significantly (P < 0.05) increased plasma glucose levels and tracer-determined glucose disappearance. Exercise-induced increases in muscle-calculated free AMP (17.7- vs. 11.8-fold), muscle lactate (3.3- vs. 1.8-fold), and plasma epinephrine were reduced by CHO ingestion. However, the exercise-induced increases in skeletal muscle AMPK[alpha]2 activity, AMPK[alpha]2 Thr(172) phosphorylation and acetyl-CoA Ser(222) phosphorylation, were essentially identical in the two trials. These findings indicate that AMPK activation in skeletal muscle during exercise in humans is not sensitive to changes in plasma glucose levels in the normal range. Furthermore, the rise in plasma epinephrine levels in response to exercise was greatly suppressed by CHO ingestion without altering AMPK signaling, raising the possibility that epinephrine does not directly control AMPK activity during muscle contraction under these conditions in vivo. adenosine monophosphate-activated protein kinase; acetyl-coenzyme A carboxylase; contraction; glucose uptake; metabolism doi:10.1152/ajpendo.00023.2006.

Aim: The primary aim of this study was to investigate whether ascorbic acid (AA) supplementation improves postprandial glucose responses under free‐living conditions in individuals with type 2 diabetes. A secondary aim was to investigate the effect of AA supplementation on blood pressure. Materials and methods: A total of 31 individuals with type 2 diabetes (26 males and 5 females; aged 61.8 ± 6.8 years; duration of diabetes, 5.6 ± 4.6 years; HbA1c, 7.6% ± 0.7% [mean ± SD]) were enrolled in a randomized cross‐over study involving 4 months of supplementation with oral AA (2 × 500 mg/d) or placebo. Participants wore continuous glucose monitors for 48 hours and consumed standardized meals pre‐ and post‐supplementation. Measurements included postprandial glucose incremental areas under the curve (iAUC), duration of day in hyper‐ and hypo‐glycaemia status, average 24‐hour and daily postprandial glucose concentrations, HbA1c, insulin, blood pressure (BP) and oxidative stress (F2‐isoprostanes). Results: Following AA supplementation, significant decreases were observed in daily postprandial glucose iAUC (−36%), in duration of day with hyperglycaemia (−2.8 h/d) and postprandial hyperglycaemia (−1.7 h/d), in average 24‐hour glucose (−0.8 mmol/L) and daily postprandial glucose (−1.1 mmol/L) concentrations, in systolic (−7 mm Hg) and diastolic (−5 mm Hg) blood pressures and in a specific fraction of free plasma F2‐isoprostanes (−47 pg/mL) as compared to placebo. Conclusions: Individuals with type 2 diabetes experienced improved postprandial and 24‐hour glycaemia and decreased BP after 4 months of AA supplementation as compared to placebo. These findings offer evidence for the proposed use of AA as an adjunct therapy to improve glycaemic and BP control in individuals with type 2 diabetes. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to determine in human skeletal muscle whether a single exercise bout and 7 days of consecutive endurance (cycling) training 1) increased insulin-stimulated Akt pSer473 and 2) altered the abundance of the protein tyrosine phosphatases (PTPases), PTP1B and SHP2. In healthy, untrained men (n = 8; 24 ± 1 yr), glucose infusion rate during a hyperinsulinemic euglycemic clamp, when compared with untrained values, was not improved 24 h following a single 60-min bout of endurance cycling but was significantly increased (-30%; P < 0.05) 24 h following completion of 7 days of exercise training. Insulin-stimulated Akt pSer473 was -50% higher (P < 0.05) 24 h following the acute bout of exercise, with this effect remaining after 7 days of training (P < 0.05). Insulin-stimulated insulin receptor and insulin receptor substrate-i tyrosine phosphorylation were not altered 24 h after acute exercise and short-term training. Insulin did not acutely regulate the localization of the PTPases, PTP1B or SHP2, although cytosolic protein abundance of SHP2 was increased (P < 0.05; main effect) 24 h following acute exercise and short-term training. In conclusion, insulin-sensitive Akt pSer473 and cytosolic SHP2 protein abundance are higher after acute exercise and short-term training, and this effect appears largely due to the residual effects of the last bout of prior exercise. The significance of exercise-induced alterations in cytosolic SHP2 and insulin-stimulated Akt pSer473 on the improvement in insulin sensitivity requires further elucidation. [ABSTRACT FROM AUTHOR]

Key points Testosterone, the major androgen, influences the reproductive and non‐reproductive systems in males and females via binding to the androgen receptor (AR). Both circulating endogenous testosterone and muscle AR protein content are positively associated with muscle mass and strength in males, but there is no such evidence in females. Here, we tested whether circulating testosterone levels were associated with muscle mass, function, or the muscle anabolic response to resistance training in pre‐menopausal females. Twenty‐seven pre‐menopausal, untrained females (aged 23.5 ± 4.8 years) underwent a 12‐week resistance training programme. Muscle strength, size, power, and plasma and urine androgen hormone levels were measured. Skeletal muscle biopsies were collected before and after the training programme to quantify the effect of resistance training on AR content and nuclear localisation. Primary muscle cell lines were cultured from a subset (n = 6) of the participants’ biopsies and treated with testosterone to investigate its effect on myotube diameter, markers of muscle protein synthesis and AR cellular localisation. Physiological levels of total testosterone were not associated with muscle mass or strength at baseline or with the changes in muscle mass and strength that occurred in response to resistance training in our cohort of pre‐menopausal females. In contrast, bioavailable testosterone and the proportion of nuclear‐localised AR were positively associated with skeletal muscle mass and strength in pre‐menopausal females. In vitro, supra‐physiological doses of testosterone increased myocyte diameter, but this did not occur via the Akt/mTOR pathway as previously suggested. Instead, we show a marked increase in AR nuclear localisation with testosterone administration in vitro. Total circulating testosterone was not related to muscle mass or strength before or after resistance training in pre‐menopausal females. Bioavailable testosterone was positively related to exercise‐induced muscle hypertrophy in pre‐menopausal females. In vivo nuclear localisation of the androgen receptor was positively related to muscle mass in pre‐menopausal females at baseline, but not to resistance training‐induced hypertrophy. Testosterone treatment induced androgen receptor nuclear translocation but did not induce mTOR signalling in primary skeletal myocytes cultured from pre‐menopausal female muscle. [ABSTRACT FROM AUTHOR]

The uptake and metabolism of glucose by skeletal muscle is a major determinant of whole body glucose homeostasis. Contraction is a strong stimulus of muscle glucose uptake that still occurs in insulin-resistant muscle. The intramuscular signaling pathways associated with contraction-mediated muscle glucose uptake are not fully understood but are separate from insulin signaling. The effects of NOS inhibition on contraction-mediated glucose uptake have yielded contradictory results due to systemic effects of NOS inhibition and measurements being made after rather than during contraction. In this study we examined the effect of local infusion of L-NAME (5µM) into one rat hindleg via the epigastric artery during muscle contraction (35V field stimulation, 0.1 msec pulses at 2Hz). Measurements included systemic blood pressure, heart rate, muscle contraction force, femoral blood flow, capillary recruitment (by contrast-enhanced ultrasound), muscle glucose uptake (by ³H-2-deoxyglucose uptake), muscle NOS activity, muscle nitrate and nitrite content (NOx), and AMPK signaling (AMPKα Thr 172 phosphorylation, ACCβ Ser222 phosphorylation and nNOS Ser 1412 phosphorylation). Local L-NAME infusion had no effect on blood pressure or heart rate indicating there were no systemic actions. The contraction-mediated increase in NOS activity and NOx content in the L-NAME treated leg were reversed while the nNOS phosphorylation remained increased. Since, NOS activity measurements from muscle at the end of the experiments were made in vitro in the absence of L-NAME, the results suggest that L-NAME in vivo has other actions than simply acting as a competitive inhibitor of NOS. The contraction-mediated increase in AMPKα and ACCβ phosphorylation, and muscle contractile force were unaffected by L-NAME infusion. L-NAME caused a significant (P<0.05) decrease (30%) in femoral blood flow but not capillary recruitment during contraction and significantly (P<0.001) reduced the contraction-mediated glucose uptake by (32%). In conclusion, NOS inhibition attenuated increases in skeletal muscle glucose uptake without influencing capillary recruitment or AMPK signaling. This suggests that nitric oxide is independently involved in the signaling pathway for contraction-mediated skeletal muscle glucose uptake distal to glucose delivery. [ABSTRACT FROM AUTHOR]

Cardiomyocyte calcium homeostasis is a tightly regulated process. The mitochondrial calcium uniporter (MCU) complex can buffer elevated cytosolic Ca 2+ levels and consists of pore-forming proteins including MCU, and various regulatory proteins such as mitochondrial calcium uptake proteins 1 and 2 (MICU1/2). The stoichiometry of these proteins influences the sensitivity to Ca 2+ and the activity of the complex. However, the factors that regulate their gene expression remain incompletely understood. Long noncoding RNAs (lncRNAs) regulate gene expression through various mechanisms, and we recently found that the lncRNA Tug1 increased the expression of Mcu and associated genes. To further explore this, we performed antisense LNA knockdown of Tug1 ( Tug1 KD) in H9c2 rat cardiomyocytes. Tug1 KD increased MCU protein expression, yet pyruvate dehydrogenase dephosphorylation, which is indicative of mitochondrial Ca 2+ uptake, was not enhanced. However, RNA-seq revealed that Tug1 KD increased Mcu along with differential expression of >1,000 genes including many related to Ca 2+ regulation pathways in the heart. To understand the effect of this on Ca 2+ signaling, we measured phosphorylation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and its downstream target cAMP Response Element-Binding protein (CREB), a transcription factor known to drive Mcu gene expression. In response to a Ca 2+ stimulus, the increase in CaMKII and CREB phosphorylation was attenuated by Tug1 KD. Inhibition of CaMKII, but not CREB, partially prevented the Tug1 KD-mediated increase in Mcu . Together, these data suggest that Tug1 modulates MCU expression via a mechanism involving CaMKII and regulates cardiomyocyte Ca 2+ signaling, which could have important implications for cardiac function. NEW & NOTEWORTHY Calcium is essential for signaling, excitation contraction, and energy homeostasis in the heart. Despite this, molecular regulators of these processes are not completely understood. We report that knockdown of lncRNA Tug1 alters the calcium handling transcriptome and increases mitochondrial calcium uniporter expression via a mechanism involving CaMKII. As overexpression of MCU is known to be protective against pathological cardiac remodeling, targeting Tug1 may be a potential strategy for treating cardiovascular disease.

This study compared the recommended dose of sodium citrate (SC, 500 mg/kg body mass) and sodium bicarbonate (SB, 300 mg/kg body mass) for blood alkalosis (blood [HCO3-]) and gastrointestinal symptoms (GIS; number and severity). Sixteen healthy individuals ingested the supplements in a randomized, crossover design. Gelatin capsules were ingested over 15 min alongside a carbohydrate-rich meal, after which participants remained seated for forearm venous blood sample collection and completion of GIS questionnaires every 30 min for 300 min. Time-course and session value (i.e., peak and time to peak) comparisons of SC and SB supplementation were performed using linear mixed models. Peak blood [HCO3-] was similar for SC (mean 34.2, 95% confidence intervals [33.4, 35.0] mmol/L) and SB (mean 33.6, 95% confidence intervals [32.8, 34.5] mmol/L, p = .308), as was delta blood [HCO3-] (SC = 7.9 mmol/L; SB = 7.3 mmol/L, p = .478). Blood [HCO3-] was ≥6 mmol/L above baseline from 180 to 240 min postingestion for SC, significantly later than for SB (120-180 min; p < .001). GIS were mostly minor, and peaked 80-90 min postingestion for SC, and 35-50 min postingestion for SB. There were no significant differences for the number or severity of GIS reported (p > .05 for all parameters). In summary, the recommended doses of SC and SB induce similar blood alkalosis and GIS, but with a different time course.

Key Points: AMP-activated protein kinase (AMPK) is considered a major regulator of skeletal muscle metabolism during exercise. However, we previously showed that, although AMPK activity increases by 8-10-fold during ∼120 min of exercise at ∼65% V ̇ O 2 peak in untrained individuals, there is no increase in these individuals after only 10 days of exercise training (longitudinal study). In a cross-sectional study, we show that there is also a lack of activation of skeletal muscle AMPK during 120 min of cycling exercise at 65% V ̇ O 2 peak in endurance-trained individuals. These findings indicate that AMPK is not an important regulator of exercise metabolism during 120 min of exercise at 65% V ̇ O 2 peak in endurance trained men. It is important that more energy is directed towards examining other potential regulators of exercise metabolism., Abstract: AMP-activated protein kinase (AMPK) is considered a major regulator of skeletal muscle metabolism during exercise. Indeed, AMPK is activated during exercise and activation of AMPK by 5-aminoimidazole-4-carboxyamide-ribonucleoside (AICAR) increases skeletal muscle glucose uptake and fat oxidation. However, we have previously shown that, although AMPK activity increases by 8-10-fold during ∼120 min of exercise at ∼65% V ̇ O 2 peak in untrained individuals, there is no increase in these individuals after only 10 days of exercise training (longitudinal study). In a cross-sectional study, we examined whether there is also a lack of activation of skeletal muscle AMPK during 120 min of cycling exercise at 65% V ̇ O 2 peak in endurance-trained individuals. Eleven untrained (UT; V ̇ O 2 peak = 37.9 ± 5.6 ml.kg -1  min -1 ) and seven endurance trained (ET; V ̇ O 2 peak = 61.8 ± 2.2 ml.kg -1  min -1 ) males completed 120 min of cycling exercise at 66 ± 4% V ̇ O 2 peak (UT: 100 ± 21 W; ET: 190 ± 15 W). Muscle biopsies were obtained at rest and following 30 and 120 min of exercise. Muscle glycogen was significantly (P < 0.05) higher before exercise in ET and decreased similarly during exercise in the ET and UT individuals. Exercise significantly increased calculated skeletal muscle free AMP content and more so in the UT individuals. Exercise significantly (P < 0.05) increased skeletal muscle AMPK α2 activity (4-fold), AMPK αThr 172 phosphorylation (2-fold) and ACCβ Ser 222 phosphorylation (2-fold) in the UT individuals but not in the ET individuals. These findings indicate that AMPK is not an important regulator of exercise metabolism during 120 min of exercise at 65% V ̇ O 2 peak in endurance trained men., (© 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The purpose of the present study was to determine in human skeletal muscle whether a single exercise bout and 7 days of consecutive endurance (cycling) training 1) increased insulin-stimulated Akt pSer(473) and 2) altered the abundance of the protein tyrosine phosphatases (PTPases), PTP1B and SHP2. In healthy, untrained men (n = 8; 24 +/- 1 yr), glucose infusion rate during a hyperinsulinemic euglycemic clamp, when compared with untrained values, was not improved 24 h following a single 60-min bout of endurance cycling but was significantly increased ( approximately 30%; P < 0.05) 24 h following completion of 7 days of exercise training. Insulin-stimulated Akt pSer(473) was approximately 50% higher (P < 0.05) 24 h following the acute bout of exercise, with this effect remaining after 7 days of training (P < 0.05). Insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation were not altered 24 h after acute exercise and short-term training. Insulin did not acutely regulate the localization of the PTPases, PTP1B or SHP2, although cytosolic protein abundance of SHP2 was increased (P < 0.05; main effect) 24 h following acute exercise and short-term training. In conclusion, insulin-sensitive Akt pSer(473) and cytosolic SHP2 protein abundance are higher after acute exercise and short-term training, and this effect appears largely due to the residual effects of the last bout of prior exercise. The significance of exercise-induced alterations in cytosolic SHP2 and insulin-stimulated Akt pSer(473) on the improvement in insulin sensitivity requires further elucidation.