Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action.

Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters skeletal muscle signaling and how exercise partially counteracts this effect. We measured parallel phenotypes and phosphoproteomes of insulin-resistant (IR) and insulin-sensitive (IS) men as they responded to exercise and insulin (n = 19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy.

Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.

In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls.

Reducing the mitochondrial oxidative burden alleviates lipid-induced muscle insulin resistance in humans.

Preclinical models suggest mitochondria-derived oxidative stress as an underlying cause of insulin resistance. However, it remains unknown whether this pathophysiological mechanism is conserved in humans. Here, we used an invasive in vivo mechanistic approach to interrogate muscle insulin action while selectively manipulating the mitochondrial redox state in humans.

Beta2-agonist Impairs Muscle Insulin Sensitivity in Persons With Insulin Resistance.

Context: Given the promising effects of prolonged treatment with beta2-agonist on insulin sensitivity in animals and nondiabetic individuals, the beta2-adrenergic receptor has been proposed as a target to counter peripheral insulin resistance. On the other hand, rodent studies also reveal that beta2-agonists acutely impair insulin action, posing a potential caveat for their use in treating insulin resistance.

Objective: To assess the impact of beta2-agonist on muscle insulin action and glucose metabolism and identify the underlying mechanism(s) in 10 insulin-resistant subjects.

AMPKγ3 Controls Muscle Glucose Uptake in Recovery From Exercise to Recapture Energy Stores.

Unlabelled: Exercise increases muscle glucose uptake independently of insulin signaling and represents a cornerstone for the prevention of metabolic disorders. Pharmacological activation of the exercise-responsive AMPK in skeletal muscle has been proven successful as a therapeutic approach to treat metabolic disorders by improving glucose homeostasis through the regulation of muscle glucose uptake. However, conflicting observations cloud the proposed role of AMPK as a necessary regulator of muscle glucose uptake during exercise.

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).

Muscle hypertrophic effect of inhaled beta -agonist is associated with augmented insulin-stimulated whole-body glucose disposal in young men.

Rodent studies highlight enhancement of glucose tolerance and insulin sensitivity as potential clinically relevant effects of chronic beta -agonist treatment. However, the doses administered to rodents are not comparable with the therapeutic doses used for humans. Thus, we investigated the physiological effects of prolonged beta -agonist treatment at inhaled doses resembling those used in respiratory diseases on insulin-stimulated whole-body glucose disposal and putative mechanisms in skeletal muscle and adipose tissue of healthy men.

Personalized phosphoproteomics identifies functional signaling.

Protein phosphorylation dynamically integrates environmental and cellular information to control biological processes. Identifying functional phosphorylation amongst the thousands of phosphosites regulated by a perturbation at a global scale is a major challenge. Here we introduce 'personalized phosphoproteomics', a combination of experimental and computational analyses to link signaling with biological function by utilizing human phenotypic variance.

The beta -adrenergic receptor - a re-emerging target to combat obesity and induce leanness?

Treatment of obesity with repurposed or novel drugs is an expanding research field. One approach is to target beta -adrenergic receptors because they regulate the metabolism and phenotype of adipose and skeletal muscle tissue. Several observations support a role for the beta -adrenergic receptor in obesity.

Salbutamol Increases Leg Glucose Uptake and Metabolic Rate but not Muscle Glycogen Resynthesis in Recovery From Exercise.

Context: Exercise blunts the effect of beta2-agonists on peripheral glucose uptake and energy expenditure. Whether such attenuation extends into recovery is unknown.

Objective: To examine the effect of a beta2-agonist on leg glucose uptake and metabolic rate in recovery from exercise.

β-Adrenergic agonist salbutamol augments hypertrophy in MHCIIa fibers and sprint mean power output but not muscle force during 11 weeks of resistance training in young men.

In this study, we examined the effect of β-agonist salbutamol at oral doses during a period of resistance training on sprint performance, quadriceps contractile function, skeletal muscle hypertrophy, fiber type composition, maximal activity of enzymes of importance for anaerobic energy turnover, and sarcoplasmic reticulum Ca handling in young men. Twenty-six men (23 ± 2 yr; means ± SD) were randomized to daily intake of oral salbutamol (16 mg/day; RES+SAL) or placebo (RES) during 11 wk of full-body resistance training 3 times/wk. Mean power output during 10-s maximal cycling increased more ( = 0.

Effect of beta -adrenergic agonist and resistance training on maximal oxygen uptake and muscle oxidative enzymes in men.

While beta -adrenoceptor stimulation has been shown to increase lean mass and to alter metabolic properties of skeletal muscle, adaptations in muscle oxidative enzymes and maximal oxygen uptake ( O ) in response to beta -adrenergic agonist treatment are inadequately explored in humans, particularly in association with resistance training. Herein, we investigated beta -adrenergic-induced changes in O , leg and arm composition, and muscle content of oxidative enzymes in response to treatment with the selective beta -adrenergic agonist terbutaline with and without concurrent resistance training in young men. Forty-six subjects were randomized to 4 weeks of lifestyle maintenance (n = 23) or resistance training (n = 23).

In-season adaptations to intense intermittent training and sprint interval training in sub-elite football players.

This study investigated the in-season effect of intensified training comparing the efficacy of duration-matched intense intermittent exercise training with sprint interval training in increasing intermittent running performance, sprint ability, and muscle content of proteins related to ion handling and metabolism in football players. After the first two weeks in the season, 22 sub-elite football players completed either 10 weeks of intense intermittent training using the 10-20-30 training concept (10-20-30, n = 12) or sprint interval training (SIT, n = 10; work/rest ratio: 6-s/54-s) three times weekly, with a ~20% reduction in weekly training time. Before and after the intervention, players performed a Yo-Yo intermittent recovery test level 1 (Yo-Yo IR1) and a 30-m sprint test.

β2-Agonist Induces Net Leg Glucose Uptake and Free Fatty Acid Release at Rest but Not During Exercise in Young Men.

Objective: The role of selective β2-adrenergic stimulation in regulation of leg glucose uptake and free fatty acid (FFA) balance is inadequately explored in humans. The objective of this study was to investigate β2-adrenergic effects on net leg glucose uptake and clearance, as well as FFA balance at rest and during exercise.

Design: The study was a randomized, placebo-controlled crossover trial where 10 healthy men received either infusion of β2-agonist terbutaline (0.

Chronic β -adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men.

Key Points: While several studies have investigated the effects of exercise training in human skeletal muscle and the chronic effect of β -agonist treatment in rodent muscle, their effects on muscle proteome signature with related functional measures in humans are still incompletely understood. Herein we show that daily β -agonist treatment attenuates training-induced enhancements in exercise performance and maximal oxygen consumption, and alters muscle proteome signature and phenotype in trained young men. Daily β -agonist treatment abolished several of the training-induced enhancements in muscle oxidative capacity and caused a repression of muscle metabolic pathways; furthermore, β -agonist treatment induced a slow-to-fast twitch muscle phenotype transition.

Beta-adrenergic stimulation increases energy expenditure at rest, but not during submaximal exercise in active overweight men.

Purpose: β-Agonists have been proposed as weight-loss treatment, because they elevate energy expenditure. However, it is unknown what effect β-agonists have on energy expenditure in overweight individuals. Furthermore, the influence of β-agonist R- and S-enantiomer ratio for the increased energy expenditure is insufficiently explored.

Mechanisms underlying enhancements in muscle force and power output during maximal cycle ergometer exercise induced by chronic β2-adrenergic stimulation in men.

The study was a randomized placebo-controlled trial investigating mechanisms by which chronic β2-adrenergic stimulation enhances muscle force and power output during maximal cycle ergometer exercise in young men. Eighteen trained men were assigned to an experimental group [oral terbutaline 5 mg/30 kg body weight (bw) twice daily (TER); n = 9] or a control group [placebo (PLA); n = 9] for a 4-wk intervention. No changes were observed with the intervention in PLA.