Exercise increases circulating GDF15 in humans

Objective: The growth differentiation factor 15 (GDF15) is a stress-sensitive circulating factor that regulates systemic energy balance. Since exercise is a transient physiological stress that has pleiotropic effects on whole-body energy metabolism, we herein explored the effect of exercise on a) circulating GDF15 levels and b) GDF15 release from skeletal muscle in humans. Methods: Seven healthy males either rested or exercised at 67% of their VO2max for 1 h and blood was sampled from the femoral artery and femoral vein before, during, and after exercise. Plasma GDF15 concentrations were determined in these samples. Results: Plasma GDF15 levels increased 34% with exercise (p < 0.001) and further increased to 64% above resting values at 120 min (p < 0.001) after the cessation of exercise. There was no difference between the arterial and venous GDF15 concentration before, during, and after exercise. During a resting control trial, GDF15 levels measured in the same subjects were unaltered. Conclusions: Vigorous submaximal exercise increases circulating GDF15 levels in humans, but skeletal muscle tissue does not appear to be the source. Keywords: Skeletal muscle, Growth differentiation factor 15, Recovery, Physical activit

Exercise increases phosphorylation of the putative mTORC2 activity readout NDRG1 in human skeletal muscle

In mice, exercise is suggested to activate the mechanistic target of rapamycin complex 2 (mTORC2) in skeletal muscle, and mTORC2 is required for normal muscle glucose uptake during exercise. Whether this translates to human skeletal muscle and what signaling pathways facilitate the exercise-induced mTORC2 activation is unknown. We herein tested the hypothesis that exercise increases mTORC2 activity in human skeletal muscle and investigated if β(2)-adrenergic receptor (AR) activation mediates exercise-induced mTORC2 activation. We examined several mTORC2 activity readouts (p-NDRG1 Thr346, p-Akt Ser473, p-mTOR S2481, and p-Akt Thr450) in human skeletal muscle biopsies after uphill walking or cycling exercise. In mouse muscles, we assessed mTORC2 activity readouts following acute activation of muscle β(2)-adrenergic or G(S) signaling and during in vivo and ex vivo muscle contractions. Exercise increased phosphorylation of NDRG1 Thr346 in human soleus, gastrocnemius, and vastus lateralis muscle, without changing p-Akt Ser473, p-Akt Thr450, and p-mTOR Ser2481. In mouse muscle, stimulation of β(2)-adrenergic or G(S) signaling and ex vivo contractions failed to increase p-NDRG1 Thr346, whereas in vivo contractions were sufficient to induce p-NDRG1 Thr346. In conclusion, the mTORC2 activity readout p-NDRG1 Thr346 is a novel exercise-responsive signaling protein in human skeletal muscle. Notably, contraction-induced p-NDRG1 Thr346 appears to require a systemic factor. Unlike exercise, and in contrast to published data obtained in cultured muscles cells, stimulation of β(2)-adrenergic signaling is not sufficient to trigger NDRG1 phosphorylation in mature mouse skeletal muscle. NEW & NOTEWORTHY The mTORC2 readout p-NDRG Thr346 is a novel exercise-responsive protein in human skeletal muscle. β2-AR and G(S) signaling are not sufficient to induce mTORC2 signaling in adult muscle. In vivo, but not ex vivo, contraction induced p-NDRG Thr346, which indicates requirement of a systemic factor for exercise-induced mTORC2 activation

ApoA-1 improves glucose tolerance by increasing glucose uptake into heart and skeletal muscle independently of AMPKα₂

Objective: Acute administration of the main protein component of high-density lipoprotein, apolipoprotein A-I (ApoA-1), improves glucose uptake in skeletal muscle. The molecular mechanisms mediating this are not known, but in muscle cell cultures, ApoA-1 failed to increase glucose uptake when infected with a dominant-negative AMP-activated protein kinase (AMPK) virus. We therefore investigated whether AMPK is necessary for ApoA-1-stimulated glucose uptake in intact heart and skeletal muscle in vivo. Methods: The effect of injection with recombinant human ApoA-1 (rApoA-1) on glucose tolerance, glucose-stimulated insulin secretion, and glucose uptake into skeletal and heart muscle with and without block of insulin secretion by injection of epinephrine (0.1 mg/kg) and propranolol (5 mg/kg), were investigated in 8 weeks high-fat diet-fed (60E%) wild-type and AMPKα2 kinase-dead mice in the overnight-fasted state. In addition, the effect of rApoA-1 on glucose uptake in isolated skeletal muscle ex vivo was studied. Results: rApoA-1 lowered plasma glucose concentration by 1.7 mmol/l within 3 h (6.1 vs 4.4 mmol/l; p < 0.001). Three hours after rApoA-1 injection, glucose tolerance during a 40-min glucose tolerance test (GTT) was improved compared to control (area under the curve (AUC) reduced by 45%, p < 0.001). This was accompanied by an increased glucose clearance into skeletal (+110%; p < 0.001) and heart muscle (+100%; p < 0.001) and an increase in glucose-stimulated insulin secretion 20 min after glucose injection (+180%; p < 0.001). When insulin secretion was blocked during a GTT, rApoA-1 still enhanced glucose tolerance (AUC lowered by 20% compared to control; p < 0.001) and increased glucose clearance into skeletal (+50%; p < 0.05) and heart muscle (+270%; p < 0.001). These improvements occurred to a similar extent in both wild-type and AMPKα2 kinase-dead mice and thus independently of AMPKα2 activity in skeletal- and heart muscle. Interestingly, rApoA-1 failed to increase glucose uptake in isolated skeletal muscles ex vivo. Conclusions: In conclusion, ApoA-1 stimulates in vivo glucose disposal into skeletal and heart muscle independently of AMPKα2. The observation that ApoA-1 fails to increase glucose uptake in isolated muscle ex vivo suggests that additional systemic effects are required

Insulin sensitization following a single exercise bout is uncoupled to glycogen in human skeletal muscle : a meta-analysis of 13 single-center human studies

Exercise profoundly influences glycemic control by enhancing muscle insulin sensitivity, thus promoting glucometabolic health. While prior glycogen breakdown so far has been deemed integral for muscle insulin sensitivity to be potentiated by exercise, the mechanisms underlying this phenomenon remain enigmatic. We have combined original data from 13 of our studies that investigated insulin action in skeletal muscle either under rested conditions or following a bout of one-legged knee extensor exercise in healthy young male individuals (n = 106). Insulin-stimulated glucose uptake was potentiated and occurred substantially faster in the prior contracted muscles. In this otherwise homogenous group of individuals, a remarkable biological diversity in the glucometabolic responses to insulin is apparent both in skeletal muscle and at the whole-body level. In contrast to the prevailing concept, our analyses reveal that insulin-stimulated muscle glucose uptake and the potentiation thereof by exercise are not associated with muscle glycogen synthase activity, muscle glycogen content, or degree of glycogen utilization during the preceding exercise bout. Our data further suggest that the phenomenon of improved insulin sensitivity in prior contracted muscle is not regulated in a homeostatic feedback manner from glycogen. Instead, we put forward the idea that this phenomenon is regulated by cellular allostatic mechanisms that elevate the muscle glycogen storage set point and enhance insulin sensitivity to promote the uptake of glucose toward faster glycogen resynthesis without development of glucose overload/toxicity or feedback inhibition

Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation

Excessive circulating FAs have been proposed to promote insulin resistance (IR) of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate IR. However, prolonged inhibition of FAOX would presumably cause lipid accumulation and thereby promote lipotoxicity. To understand the glycemic consequences of acute and prolonged FAOX inhibition, we treated mice with the carnitine palmitoyltransferase 1 (CPT-1) inhibitor, etomoxir (eto), in combination with short-term 45% high fat diet feeding to increase FA availability. Eto acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in the liver and heart within hours. Several days of FAOX inhibition by daily eto administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by eto. Lower whole-body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) protein content, diminished BAT glucose clearance, and increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat IR, and that sufficient rates of FAOX are required for maintaining liver and BAT metabolic function

pH-gated succinate secretion regulates muscle remodeling in response to exercise

In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal that initiates muscle remodeling through exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release. Upon secretion, succinate signals via its cognate receptor SUCNR1 in non-myofibrillar cells in muscle tissue to control muscle-remodeling transcriptional programs. This succinate-SUCNR1 signaling is required for paracrine regulation of muscle innervation, muscle matrix remodeling, and muscle strength in response to exercise training. In sum, we define a bioenergetic sensor in muscle that utilizes intracellular pH and succinate to coordinate tissue adaptation to exercise