Control Of Skeletal Muscle Metabolism Research Articles

AMPK activation is sufficient to increase skeletal muscle glucose uptake and glycogen synthesis but is not required for contraction-mediated increases in glucose metabolism

The AMP-activated protein kinase (AMPK) is a cellular sensor of energetics and when activated in skeletal muscle during contraction can impart changes in skeletal muscle metabolism. Therapeutics that selectively activate AMPK have been developed to lower glucose levels through increased glucose disposal rates as an approach to abrogate the hyperglycemic state of diabetes; however, the metabolic fate of glucose following AMPK activation remains unclear. We have used a combination of in vivo evaluation of glucose homeostasis and ex vivo skeletal muscle incubation to systematically evaluate metabolism following pharmacological activation of AMPK with PF-739, comparing this with AMPK activation through sustained intermittent electrical stimulation of contraction. These methods to activate AMPK result in increased glucose uptake but divergent metabolism of glucose: pharmacological activation results in increased glycogen accumulation while contraction-induced glucose uptake results in increased lactate formation and glucose oxidation. These results provide additional evidence to support a role for AMPK in control of skeletal muscle metabolism and additional insight into the potential for AMPK stimulation with small molecule direct activators.

Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism.

Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation– and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle.

The Emerging Roles of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 in Skeletal Muscle Redox Signaling and Metabolism.

Significance: Skeletal muscle is a crucial tissue to whole-body locomotion and metabolic health. Reactive oxygen species (ROS) have emerged as intracellular messengers participating in both physiological and pathological adaptations in skeletal muscle. A complex interplay between ROS-producing enzymes and antioxidant networks exists in different subcellular compartments of mature skeletal muscle. Recent evidence suggests that nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are a major source of contraction- and insulin-stimulated oxidants production, but they may paradoxically also contribute to muscle insulin resistance and atrophy. Recent Advances: Pharmacological and molecular biological tools, including redox-sensitive probes and transgenic mouse models, have generated novel insights into compartmentalized redox signaling and suggested that NOX2 contributes to redox control of skeletal muscle metabolism. Critical Issues: Major outstanding questions in skeletal muscle include where NOX2 activation occurs under different conditions in health and disease, how NOX2 activation is regulated, how superoxide/hydrogen peroxide generated by NOX2 reaches the cytosol, what the signaling mediators are downstream of NOX2, and the role of NOX2 for different physiological and pathophysiological processes. Future Directions: Future research should utilize and expand the current redox-signaling toolbox to clarify the NOX2-dependent mechanisms in skeletal muscle and determine whether the proposed functions of NOX2 in cells and animal models are conserved into humans.

The role of sphingosine‐1‐phosphate in skeletal muscle: Physiology, mechanisms, and clinical perspectives

Sphingolipids were discovered more than a century ago and were simply considered as a class of cell membrane lipids for a long time. However, after the discovery of several intracellular functions and their role in the control of many physiological and pathophysiological conditions, these molecules have gained much attention. For instance, the sphingosine-1-phosphate (S1P) is a circulating bioactive sphingolipid capable of triggering strong intracellular reactions through the family of S1P receptors (S1PRs) spread in several cell types and tissues. Recently, the role of S1P in the control of skeletal muscle metabolism, atrophy, regeneration, and metabolic disorders has been widely investigated. In this review, we summarized the knowledge of S1P and its effects in skeletal muscle metabolism, highlighting the role of S1P/S1PRs axis in skeletal muscle regeneration, fatigue, ceramide accumulation, and insulin resistance. Finally, we discussed the physical exercise role in S1P/S1PRs signaling in skeletal muscle cells, and how this nonpharmacological strategy may be prospective for future investigations due to its ability to increase S1P levels.

The Role of AMPK in the Regulation of Skeletal Muscle Size, Hypertrophy, and Regeneration.

AMPK (5’-adenosine monophosphate-activated protein kinase) is heavily involved in skeletal muscle metabolic control through its regulation of many downstream targets. Because of their effects on anabolic and catabolic cellular processes, AMPK plays an important role in the control of skeletal muscle development and growth. In this review, the effects of AMPK signaling, and those of its upstream activator, liver kinase B1 (LKB1), on skeletal muscle growth and atrophy are reviewed. The effect of AMPK activity on satellite cell-mediated muscle growth and regeneration after injury is also reviewed. Together, the current data indicate that AMPK does play an important role in regulating muscle mass and regeneration, with AMPKα1 playing a prominent role in stimulating anabolism and in regulating satellite cell dynamics during regeneration, and AMPKα2 playing a potentially more important role in regulating muscle degradation during atrophy.

Distinct roles for REV-ERBα and REV-ERBβ in oxidative capacity and mitochondrial biogenesis in skeletal muscle.

The nuclear receptors REV-ERBα and REV-ERBβ have been demonstrated to be core members of the circadian clock and participate in the regulation of a diverse set of metabolic functions. Due to their overlapping tissue expression patterns and gene expression profiles, REV-ERBβ is thought to be redundant to REV-ERBα. Recent work has highlighted REV-ERBα’s role in the regulation of skeletal muscle oxidative capacity and mitochondrial biogenesis. Considering the similarity between the REV-ERBs and the hypothesized overlap in function, we sought to determine whether REV-ERBβ-deficiency presented with a similar skeletal muscle phenotype as REV-ERBα-deficiency. Ectopic overexpression in C2C12 cells demonstrated that REV-ERBβ drives mitochondrial biogenesis and the expression of genes involved in fatty acid oxidation. Intriguingly, knock down of REV-ERBβ in C2C12 cultures also resulted in mitochondrial biogenesis and increased expression of genes involved in fatty acid β-oxidation. To determine whether these effects occurred in vivo, we examined REV-ERBβ-deficient mice and observed a similar increase in expression of genes involved in mitochondrial biogenesis and fatty acid β-oxidation. Consistent with these results, REV-ERBβ-deficient mice exhibited an altered metabolic phenotype compared to wild-type littermate controls when measured by indirect calorimetry. This likely compensated for the increased food consumption that occurred, possibly aiding in the maintenance of their weight over time. Since feeding behaviors are a direct circadian output, this study suggests that REV-ERBβ may have more subtle effects on circadian behaviors than originally identified. Furthermore, these data implicate REV-ERBβ in the control of skeletal muscle metabolism and energy expenditure and suggest that development of REV-ERBα versus REV-ERBβ selective ligands may have therapeutic utility in the treatment of metabolic syndrome.

Impact of cell‐free hemoglobin on contracting skeletal muscle oxygen pressure dynamics: Potential therapeutic role of haptoglobin

Free hemoglobin (Hb) associated with hemolytic diseases (i.e., sickle cell anemia) extravasates into vascular tissue and depletes nitric oxide (NO), which leads to impaired vascular function and could disrupt skeletal muscle metabolic control during exercise. We tested the hypothesis that: 1) free Hb would extravasate into skeletal muscle tissue impairing the contracting skeletal muscle O2 delivery/O2 utilization ratio (microvascular PO2, PO2mv) to a similar extent as that observed following NO synthase (NOS) blockade, and 2) that the Hb scavenging protein haptoglobin (Hp) would prevent Hb extravasation and inhibit these skeletal muscle tissue effects. PO2mv was measured in eight healthy rats (phosphorescence quenching) at rest and during 180s of electrically induced (1‐Hz) twitch spinotrapezius muscle contractions (experiment 1). A second subset of seven rats was also used to investigate the effects of Hb+Hp (experiment 2). For both experiments, measurements were made: 1) during control conditions, 2) following a bolus infusion of either Hb (50 mg/kg) or Hb+Hp (50 mg/kg, bound Hb), and 3) following local superfusion of NG‐nitro‐l‐arginine methyl ester (L‐NAME; 10 mg/kg). Additional experiments were completed to visualize Hb extravasation into the muscular tissue using Click chemistry techniques. There were no significant differences in the PO2mv observed at rest for any condition in either experiment (p>0.05 for all). In experiment 1, both Hb and L‐NAME reduced the PO2mv significantly during the steady‐state of muscle contractions when compared to control conditions with no differences between Hb and L‐NAME conditions (control: 24 ± 1, Hb: 21 ± 1, L‐NAME: 20 ± 1 mmHg, p<0.05). In experiment 2, only L‐NAME resulted in a significantly lower PO2mv during the steady‐state of muscle contractions (control: 25 ± 1, Hb+Hp: 22 ± 2, L‐NAME: 18 ± 1 mmHg, p<0.05). Free Hb lowered the blood‐myocyte O2 driving force to a level not significantly different from L‐NAME. However, infusing Hb bound to Hp resulted in no significant differences in steady‐state PO2mv during muscle contractions when compared to control. Surprisingly, we did not observe Hb accumulation in skeletal muscle tissue. Taken together these data suggest that free Hb impairs O2 delivery/utilization via a NO scavenging effect which would presumably disrupt oxidative metabolism and shorten the onset of fatigue during exercise. Furthermore, the unchanged PO2mv steady‐state observed following Hb+Hp further suggests that therapeutic administration of the Hb binding protein haptoglobin may restore skeletal muscle metabolic control and potentially exercise tolerance in those afflicted with hemolytic diseases.Support or Funding InformationFunded by NIH (R01HL125642) to DCI and Colorado Nutrition and Obesity Research Center (P30DK048520) award to SKF.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impact of cell-free hemoglobin on contracting skeletal muscle microvascular oxygen pressure dynamics

Free hemoglobin (Hb) associated with hemolysis extravasates into vascular tissue and depletes nitric oxide (NO), which leads to impaired vascular function and could impair skeletal muscle metabolic control during exercise. We tested the hypothesis that: 1) free Hb would extravasate into skeletal muscle tissue, reducing the contracting skeletal muscle O2 delivery/O2 utilization ratio (microvascular PO2, PO2mv) to a similar extent as that observed following NO synthase (NOS) blockade, and 2) that the Hb scavenging protein haptoglobin (Hp) would prevent Hb extravasation and inhibit these skeletal muscle tissue effects. PO2mv was measured in eight rats (phosphorescence quenching) at rest and during 180 s of electrically induced (1-Hz) twitch spinotrapezius muscle contractions (experiment 1). A second group of seven rats was also used to investigate the effects of Hb + Hp (experiment 2). For both experiments, measurements were made: 1) during control conditions, 2) following a bolus infusion of either Hb (50 mg/kg) or Hb + Hp (50 mg/kg), and 3) following local superfusion of NG-nitro-l-arginine methyl ester (L-NAME; 10 mg/kg). Additional experiments were completed to visualize Hb extravasation into the muscular tissue using Click chemistry techniques. There were no significant differences in the PO2mv observed at rest for any condition in either experiment (p > 0.05 for all). In experiment 1, both Hb and L-NAME reduced the PO2mv significantly during the steady-state of muscle contractions when compared to control conditions with no differences between Hb and L-NAME (control: 24 ± 1, Hb: 21 ± 1, L-NAME: 20 ± 1 mmHg, p < 0.05). In experiment 2, only L-NAME resulted in a significantly lower PO2mv during the steady-state of muscle contractions (control: 25 ± 1, Hb + Hp: 22 ± 2, L-NAME: 18 ± 1 mmHg, p < 0.05). Free Hb lowered the blood-myocyte O2 driving force to a level not significantly different from L-NAME. However, infusing Hb bound to Hp resulted in no significant differences in steady-state PO2mv during muscle contractions when compared to control. Surprisingly, we did not observe Hb accumulation in skeletal muscle tissue. Taken together these data suggests that free Hb impairs O2 delivery/utilization via a NO scavenging effect. Furthermore, the unchanged PO2mv steady-state observed following Hb + Hp further indicates that vascular compartmentalization of Hb by the scavenger protein haptoglobin may improve skeletal muscle metabolic control and potentially exercise tolerance in those afflicted with hemolytic diseases.

Using exercise training to understand control of skeletal muscle metabolism.

Bengt Saltin believed that exercise was the unsurpassed tool to study human integrative physiology. He demonstrated this over the course of his career by employing physical training as a model to advance our understanding of skeletal muscle metabolic control and the impact of physical activity on performance and health. Bengt was also a pioneer in advocating the concept of exercise is medicine. His scientific curiosity was perhaps exceeded only by his generosity.

High-Intensity Exercise Training for the Prevention of Type 2 Diabetes Mellitus

Aerobic exercise training and diet are recommended for the primary prevention of type 2 diabetes mellitus and cardiovascular disease. The American Diabetes Association (ADA) recommends that adults with prediabetes engage in ≥ 150 minutes per week of moderate activity and target a 7% weight loss. However, traditional moderate-intensity (MI) exercise training programs are often difficult to sustain for prediabetic adults; a commonly cited barrier to physical activity in this population is the “lack of time” to exercise. When matched for total energy expenditure, high-intensity (HI) exercise training has a lower overall time commitment compared with traditional low-intensity (LI) or MI exercise training. Several recent studies comparing HI exercise training with LI and MI exercise training reported that HI exercise training improves skeletal muscle metabolic control and cardiovascular function in a comparable and/or superior way relative to LI and MI exercise training. Although patients can accrue all exercise benefits by performing LI or MI activities such as walking, HI activities represent a time-efficient alternative to meeting physical activity guidelines. High-intensity exercise training is a potent tool for improving cardiometabolic risk for prediabetic patients with limited time and may be prescribed when appropriate.

Physiological adaptations to low‐volume, high‐intensity interval training in health and disease

Exercise training is a clinically proven, cost-effective, primary intervention that delays and in many cases prevents the health burdens associated with many chronic diseases. However, the precise type and dose of exercise needed to accrue health benefits is a contentious issue with no clear consensus recommendations for the prevention of inactivity-related disorders and chronic diseases. A growing body of evidence demonstrates that high-intensity interval training (HIT) can serve as an effective alternate to traditional endurance-based training, inducing similar or even superior physiological adaptations in healthy individuals and diseased populations, at least when compared on a matched-work basis. While less well studied, low-volume HIT can also stimulate physiological remodelling comparable to moderate-intensity continuous training despite a substantially lower time commitment and reduced total exercise volume. Such findings are important given that 'lack of time' remains the most commonly cited barrier to regular exercise participation. Here we review some of the mechanisms responsible for improved skeletal muscle metabolic control and changes in cardiovascular function in response to low-volume HIT. We also consider the limited evidence regarding the potential application of HIT to people with, or at risk for, cardiometabolic disorders including type 2 diabetes. Finally, we provide insight on the utility of low-volume HIT for improving performance in athletes and highlight suggestions for future research.

Fuel oxidation during human walking

Human adults walk at a characteristic speed, but the mechanisms responsible for this ubiquitous and reproducible behavior remain unknown. In this study, preferred walking speed (PWS) was 4.7 ± 0.1 km h −1 in 12 overnight-fasted adults, mean age 30.0 ± 2.6 years. Indirect calorimetry was used to measure fuel oxidation during level treadmill walking from 3.2 to 7.2 km h −1 progressively increased at increments of 0.8 km h −1 and 10.0-min intervals. Corroborating many previous reports, the O 2 cost of transport (mL O 2 kg −1 km −1) was numerically lowest at 4.8 km h −1, near PWS, but was not significantly different than 5.6 km h −1. The impact of walking speed on the fuel selection of skeletal muscle was much more dramatic. At speeds less than or equal to PWS, muscle carbohydrate (CHO) oxidation rates were quite low, in the range that could be matched by gluconeogenesis. Above 4.8 km h −1, CHO oxidation rate increased abruptly and tracked the perception of effort (RPE). Stepwise linear regression revealed that CHO oxidation explained 70% of the variance in RPE, and speed provided an additional 4%. In contrast, the other variables included in the analysis, fat oxidation rate, heart rate, and O 2 cost of transport, contributed no additional explained variance in RPE. We conclude that PWS is just below a threshold speed, above which CHO oxidation abruptly increases. The central nervous system may be guided by the perception of effort in selecting a PWS that minimizes dependence on CHO oxidation. We further conclude that skeletal muscle metabolic control is an important factor to be taken into account by the central nervous system motor control of human locomotion.

Nitric Oxide and Control of Skeletal Muscle Metabolism

Nitric Oxide and Control of Skeletal Muscle Metabolism

Nitric Oxide and Control of Skeletal Muscle Metabolism

Nitric Oxide and Control of Skeletal Muscle Metabolism

Role of AMP-Activated Protein Kinase in the Control of Glucose Homeostasis

Skeletal muscle insulin resistance is a hallmark feature of Type 2 diabetes. Physical exercise/muscle contraction elicits an insulin-independent increase in glucose transport and perturbation of this pathway may bypass defective insulin signaling. To date, the exercise-responsive signaling molecules governing glucose metabolism in skeletal muscle are largely unknown. AMP-activated protein kinase (AMPK) has been suggested as one of the exercise-responsive signaling molecules involved in glucose homeostasis and consequently it has been heavily explored as a pharmacological target for the treatment of Type 2 diabetes. AMPK exists in heterotrimeric complexes composed of a catalytic alpha-subunit and regulatory beta- and gamma-subunits. The gamma3-isoform of AMPK is expressed specifically in skeletal muscle of humans and rodents and this tissue specific expression pattern offers selectivity in AMPK action. Furthermore, mutations in the AMPK gamma3-isoform may provide protection from diet-induced insulin resistance by increasing lipid oxidation in the presence of increased lipid supply. This review highlights the current understanding of the role of the regulatory AMPK gamma3-isoform in the control of skeletal muscle metabolism.

Vascular and endocrine control of muscle metabolism.

Important differences exist between perfused and incubated (or perifused) skeletal muscle preparations with regard to their metabolism and control. A growing body of evidence suggests that the differences may be due to the role played by the vascular system. In the constant-flow perfused rat hindlimb preparation, a group of vasoconstrictors has been identified that enhance muscle metabolism and aerobic contractility. Another group of vasoconstrictors decrease muscle metabolism and aerobic contractility even though perfusate flow remains constant. All effects of both groups of vasoconstrictors are opposed by vasodilators. Because none of the vasoconstrictor effects is evident when isolated muscles are incubated or perifused, involvement of an active vascular system is indicated. Although some hormones may act directly on muscle by purely endocrine effects, a vascular component of their actions is now emerging. Mechanisms to account for vascular control of perfused skeletal muscle metabolism may involve 1) functional vascular shunts where the proportion of flow processed by these is regulated by site-specific vasomodulators, 2) a direct response to a change in the rate of supply of nutrients and removal of products, and 3) a signal substance released by vascular tissue in association with vasoconstriction that interacts with surrounding skeletal muscle cells. Impaired control at the level of the vascular system may have implications for long-term access of nutrients and hormones and therefore the control of skeletal muscle metabolism and contractile performance.