Myokine Secretion following an Aerobic Exercise Intervention in Individuals with Type 2 Diabetes with or without Exercise Resistance.

Type 2 diabetes (T2D) is characterized by muscle metabolic dysfunction that exercise can minimize, but some patients do not respond to an exercise intervention. Myokine secretion is intrinsically altered in patients with T2D, but the role of myokines in exercise resistance in this patient population has never been studied. We sought to determine if changes in myokine secretion were linked to the response to an exercise intervention in patients with T2D. The participants followed a 10-week aerobic exercise training intervention, and patients with T2D were grouped based on muscle mitochondrial function improvement (responders versus non-responders). We measured myokines in serum and cell-culture medium of myotubes derived from participants pre- and post-intervention and in response to an in vitro model of muscle contraction. We also quantified the expression of genes related to inflammation in the myotubes pre- and post-intervention. No significant differences were detected depending on T2D status or response to exercise in the biological markers measured, with the exception of modest differences in expression patterns for certain myokines (IL-1ß, IL-8, IL-10, and IL-15). Further investigation into the molecular mechanisms involving myokines may explain exercise resistance with T2D; however, the role in metabolic adaptations to exercise in T2D requires further investigation.

Exercise training reduces circulating cytokines in male patients with coronary artery disease and type 2 diabetes: A pilot study.

Low-grade inflammation is central to coronary artery disease (CAD) and type 2 diabetes (T2D) and is reduced by exercise training. The objective of this study was to compare the anti-inflammatory potential of moderate-to-vigorous intensity continuous training (MICT) and high-intensity interval training (HIIT) in patients with CAD with or without T2D. The design and setting of this study is based on a secondary analysis of registered randomized clinical trial NCT02765568. Male patients with CAD were randomly assigned to either MICT or HIIT, with subgroups divided according to T2D status (non-T2D-HIIT n = 14 and non-T2D-MICT n = 13; T2D-HIIT n = 6 and T2D-MICT n = 5). The intervention was a 12-week cardiovascular rehabilitation program consisting of either MICT or HIIT (twice weekly sessions) and circulating cytokines measured pre- and post-training as inflammatory markers. The co-occurrence of CAD and T2D was associated with increased plasma IL-8 (p = 0.0331). There was an interaction between T2D and the effect of the training interventions on plasma FGF21 (p = 0.0368) and IL-6 (p = 0.0385), which were further reduced in the T2D groups. An interaction between T2D, training modalities, and the effect of time (p = 0.0415) was detected for SPARC, with HIIT increasing circulating concentrations in the control group, while lowering them in the T2D group, and the inverse occurring with MICT. The interventions also reduced plasma FGF21 (p = 0.0030), IL-6 (p = 0.0101), IL-8 (p = 0.0087), IL-10 (p < 0.0001), and IL-18 (p = 0.0009) irrespective of training modality or T2D status. HIIT and MICT resulted in similar reductions in circulating cytokines known to be increased in the context of low-grade inflammation in CAD patients, an effect more pronounced in patients with T2D for FGF21 and IL-6.

The bidirectional relationship between AMPK pathway activation and myokine secretion in skeletal muscle: How it affects energy metabolism.

Myokines are peptides and proteins secreted by skeletal muscle cells, into the interstitium, or in the blood. Their regulation may be dependent or independent of muscle contraction to induce a variety of metabolic effects. Numerous myokines have been implicated in influencing energy metabolism via AMP-activated protein kinase (AMPK) signalling. As AMPK is centrally involved in glucose and lipid metabolism, it is important to understand how myokines influence its signalling, and vice versa. Such insight will better elucidate the mechanism of metabolic regulation during exercise and at rest. This review encompasses the latest research conducted on the relationship between AMPK signalling and myokines within skeletal muscles via autocrine or paracrine signalling.

Placental superoxide dismutase 3 mediates benefits of maternal exercise on offspring health.

Poor maternal diet increases the risk of obesity and type 2 diabetes in offspring, adding to the ever-increasing prevalence of these diseases. In contrast, we find that maternal exercise improves the metabolic health of offspring, and here, we demonstrate that this occurs through a vitamin D receptor-mediated increase in placental superoxide dismutase 3 (SOD3) expression and secretion. SOD3 activates an AMPK/TET signaling axis in fetal offspring liver, resulting in DNA demethylation at the promoters of glucose metabolic genes, enhancing liver function, and improving glucose tolerance. In humans, SOD3 is upregulated in serum and placenta from physically active pregnant women. The discovery of maternal exercise-induced cross talk between placenta-derived SOD3 and offspring liver provides a central mechanism for improved offspring metabolic health. These findings may lead to novel therapeutic approaches to limit the transmission of metabolic disease to the next generation.

The effects of acute BPA exposure on skeletal muscle mitochondrial function and glucose metabolism.

Bisphenol A (BPA) is an environmental pollutant that has been associated with adverse health effects including skeletal muscle insulin resistance, a major contributor to the pathogenesis of type 2 diabetes (T2D). Early mitochondrial dysfunction and oxidative stress are linked to impaired glucose metabolism in skeletal muscle. In this study, we investigated the effects of BPA on skeletal muscle mitochondrial function and insulin sensitivity. L6 myotubes were treated with BPA (1 nM-105 nM) during the last 24 h of differentiation. Following exposure to 105 nM of BPA, resting and maximal oxygen consumption rates were decreased, whereas mitochondrial proton leak was increased. Overall metabolic activity, measured by redox ability, was decreased in L6 myotubes exposed to 105 nM of BPA. At this concentration, insulin-stimulated glucose uptake was increased, which corresponded to an increased phosphorylation of the insulin signaling protein Akt, and increased glycolysis measured by extracellular acidification rate (ECAR). Acute BPA exposure did not alter levels of oxidative stress markers in muscle cells, but significantly increased mitochondrial proton leak, which is known to be involved in decreased ROS production. The effects of BPA on glucose uptake, but not mitochondrial function, were reversed by the use of an estrogen receptor antagonist. These results suggest that acute exposure of L6 myotubes at only high concentrations of BPA alters glucose metabolism, which is likely a compensatory response to reduced mitochondrial energy production capacity.

Effects of PCB126 on Adipose-to-Muscle Communication in an in Vitro Model.

BACKGROUND: Exposure to coplanar polychlorinated biphenyls (PCBs) is linked to the development of insulin resistance. Previous studies suggested PCB126 alters muscle mitochondrial function through an indirect mechanism. Given that PCBs are stored in fat, we hypothesized that PCB126 alters adipokine secretion, which in turn affects muscle metabolism. OBJECTIVES: We determined a) the impacts of PCB126 exposure on adipocyte cytokine/adipokine secretion in vitro; b) whether adipocyte-derived factors alter glucose metabolism and mitochondrial function in myotubes when exposed to PCB126; and c) whether preestablished insulin resistance alters the metabolic responses of adipocytes exposed to PCB126 and the communication between adipocytes and myotubes. METHODS: 3T3-L1 adipocytes were exposed to PCB126 (1-100 nM) in two insulin sensitivity conditions [insulin sensitive (IS) and insulin resistant (IR) adipocytes], followed by the measurement of secreted adipokines, mitochondrial function, and insulin-stimulated glucose uptake. Communication between adipocytes and myotubes was reproduced by exposing C2C12 myotubes or mouse primary myotubes to conditioned medium (CM) derived from IS or IR 3T3-L1 adipocytes exposed to PCB126. Mitochondrial function and insulin-stimulated glucose uptake were then determined in myotubes. RESULTS: IR 3T3-L1 adipocytes treated with PCB126 had significantly higher adipokine (adiponectin, IL-6, MCP-1, TNF-α) secretion and lower mitochondrial function, glucose uptake, and glycolysis. However, PCB126 did not significantly alter these parameters in IS adipocytes. Altered energy metabolism in IR 3T3-L1 adipocytes was linked to lower phosphorylation of AMP-activated protein kinase (p-AMPK) and higher superoxide dismutase 2 levels, an enzyme involved in reactive oxygen species detoxification. Myotubes exposed to the CM from PCB126-treated IR adipocytes had lower glucose uptake, with no alteration in glycolysis or mitochondrial function. Interestingly, p-AMPK levels were higher in myotubes exposed to the CM of PCB126-treated IR adipocytes. DISCUSSION: Taken together, these data suggest that increased adipokine secretion from IR adipocytes exposed to PCB126 might explain impaired glucose uptake in myotubes. https://doi.org/10.1289/EHP7058.

Plasma Myokine Concentrations After Acute Exercise in Non-obese and Obese Sedentary Women.

Exercise and physical activity levels influence myokine release from skeletal muscle and contribute to circulating concentrations. Indeed, many myokines, including interleukin (IL)-6, IL-15, secreted protein acidic rich in cysteine (SPARC), and fibroblast growth factor (FGF) 21 are higher in the circulation after an exercise bout. Since these peptides modulate muscle metabolism and can also be targeted toward other tissues to induce adaptations to energy demand, they are of great interest regarding metabolic diseases. Therefore, we set out to compare, in six women with obesity (BMI ≥30 kg/m2) and five healthy women (BMI 22-29.9 kg/m2), the effect of an acute bout of moderate-intensity, continuous cycling exercise (60 min, 60% VO2peak) on the release of myokines (IL-6, IL-8, IL-10, IL-13, IL-15, SPARC, and FGF21) in plasma for a 24-h time course. We found that plasma IL-8 and SPARC levels were reduced in the group of women with obesity, whereas plasma IL-13 concentrations were elevated in comparison to non-obese women both before and after the exercise bout. We also found that plasma FGF21 concentration during the 24 h following the bout of exercise was regulated differently in the non-obese in comparison to obese women. Plasma concentrations of FGF21, IL-6, IL-8, IL-15, and IL-18 were regulated by acute exercise. Our results confirm the results of others concerning exercise regulation of circulating myokines while providing insight into the time course of myokine release in circulation after an acute exercise bout and the differences in circulating myokines after exercise in women with or without obesity.

Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation.

Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOT deficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limiting enzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy.

Examination of the Myokine Response in Pregnant and Non-pregnant Women Following an Acute Bout of Moderate-Intensity Walking.

BACKGROUND: It is recommended that women accumulate 150-min of weekly moderate-intensity physical activity (MPA) when pregnant. Engaging in regular physical activity (PA) confers many health benefits to both the mother and the fetus. However, the molecular mechanisms by which these health benefits are bestowed are not well understood. One potential factor that may be contributing to the observed benefits is myokines, which are small peptides secreted by skeletal muscles. In the non-pregnant population, myokines are believed to be involved in the molecular mechanisms resulting from PA. The objective of this study was to characterize and compare the myokine profile of pregnant and non-pregnant women, after an acute bout of MPA. METHODS: Pregnant (n = 13) and non-pregnant (n = 17) women were recruited from the Ottawa region to undergo a treadmill walking session at moderate-intensity (40-60% heart rate reserve). Pre- and post-exercise serum samples were taken, and a set of 15 myokines were analyzed although only 10 were detected. IL-6 was analyzed using a high-sensitivity assay, while FGF21, EPO, BDNF, Fractalkine, IL-15, SPARC, FABP-3, FSTL-1, and oncostatin were analyzed using various multiplex assays. RESULTS: The pregnant and non-pregnant groups did not differ in terms of age, height, non/pre-pregnancy weight, BMI, and resting heart rate. Baseline levels of EPO and oncostatin were higher in the pregnant group while FGF21 was higher in the non-pregnant group. Circulating levels of three myokines, FGF21, EPO, and IL-15 significantly increased in response to the acute exercise in the pregnant group. Non-pregnant women exhibited an increase in three myokines, FABP-3, FSTL-1, and oncostatin, while one myokine, EPO, decreased post-exercise. SPARC, fractalkine and BDNF were shown to increase post-exercise regardless of pregnancy status while the response for BDNF was more pronounced in the non-pregnant group. CONCLUSION: This is the first study examining myokine response following an acute bout of PA in pregnancy. Moderate intensity PA, which is recommended during pregnancy, elicited an increase in four myokines post-compared to pre-exercise in the pregnant group. Further research is warranted to understand the role of myokines in pregnancy.

Polychlorinated biphenyl 126 exposure in rats alters skeletal muscle mitochondrial function.

In the past few years, polychlorinated biphenyls (PCBs), a class of environmental pollutants, have been associated with metabolism dysregulation. Muscle is one of the key regulators of metabolism because of its mass and its important role in terms of glucose consumption and glucose storage. It has been shown that muscle alterations, such as oxidative stress and mitochondrial dysfunction, contribute significantly to the development of metabolic diseases. No study has yet investigated the toxicological effect of PCBs on muscle mitochondrial function and oxidative stress in vivo. The aim of this study was to assess the effect of PCB126 in vivo exposure (single dose of 1.05 µmol/kg) on muscle mitochondrial function and oxidative stress in rats. PCB126-treated rats showed a marked increase in Cyp1a1 mRNA levels in skeletal muscles in association with a 40% reduction in state 3 oxygen consumption rate measured with complex I substrates in permeabilized muscle fibers. Furthermore, PCB126 exposure altered the expression of some enzymes involved in ROS detoxification such as catalase and glutaredoxin 2. Our results highlight for the first time a toxic effect of coplanar PCBs on skeletal muscle mitochondrial function and oxidative stress. This suggests that acute PCB exposure, by affecting muscle metabolism, could contribute to the development of metabolic disorders. Studies are needed to determine if lower-level but longer-term PCB exposure exhibits the same effect.