Anders Rinnov

The miRNA Plasma Signature in Response to Acute Aerobic Exercise and Endurance Training

MiRNAs are potent intracellular posttranscriptional regulators and are also selectively secreted into the circulation in a cell-specific fashion. Global changes in miRNA expression in skeletal muscle in response to endurance exercise training have been reported. Therefore, our aim was to establish the miRNA signature in human plasma in response to acute exercise and chronic endurance training by utilizing a novel methodological approach. RNA was isolated from human plasma collected from young healthy men before and after an acute endurance exercise bout and following 12 weeks of endurance training. Global miRNA (742 miRNAs) measurements were performed as a screening to identify detectable miRNAs in plasma. Using customized qPCR panels we quantified the expression levels of miRNAs detected in the screening procedure (188 miRNAs). We demonstrate a dynamic regulation of circulating miRNA (ci-miRNA) levels following 0 hour (miR-106a, miR-221, miR-30b, miR-151-5p, let-7i, miR-146, miR-652 and miR-151-3p), 1 hour (miR-338-3p, miR-330-3p, miR-223, miR-139-5p and miR-143) and 3 hours (miR-1) after an acute exercise bout (P<0.00032). Where ci-miRNAs were all downregulated immediately after an acute exercise bout (0 hour) the 1 and 3 hour post exercise timepoints were followed by upregulations. In response to chronic training, we identified seven ci-miRNAs with decreased levels in plasma (miR-342-3p, let-7d, miR-766, miR-25, miR-148a, miR-185 and miR-21) and two miRNAs that were present at higher levels after the training period (miR-103 and miR-107) (P<0.00032). In conclusion, acute exercise and chronic endurance training, likely through specific mechanisms unique to each stimulus, robustly modify the miRNA signature of human plasma.

Plasma follistatin is elevated in patients with type 2 diabetes: relationship to hyperglycemia, hyperinsulinemia, and systemic low-grade inflammation

Plasma follistatin is elevated in patients with low‐grade inflammation and insulin resistance as observed with polycystic ovary syndrome. In the present study, we evaluated plasma follistatin in patients with type 2 diabetes characterised by low‐grade inflammation and assessed the acute effects of hyperglycemia, hyperinsulinemia and LPS on plasma follistatin.

Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy

Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men undergoing ADT for prostate cancer and ten healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic-hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy X-ray absorptiometry and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P<0.0001). The patients and controls demonstrated an increase in peripheral tissue insulin sensitivity of 14 and 11% respectively (P<0.05), with no effect on hepatic insulin sensitivity (P=0.32). Muscle protein content of GLUT4 (SLC2A4) and total AKT (AKT1) was also increased in response to the training (P<0.05 and P<0.01 respectively). Body weight (P<0.0001) and whole-body fat mass (FM) (P<0.01) were reduced, while lean body mass (P=0.99) was unchanged. Additionally, reductions were observed in abdominal (P<0.01), subcutaneous (P<0.05), and visceral (P<0.01) FM amounts. The concentrations of plasma markers of systemic inflammation were unchanged in response to the training. No group × time interactions were observed, except for thigh intermuscular adipose tissue (IMAT) (P=0.01), reflecting a significant reduction in the amount of IMAT in the controls (P<0.05) not observed in the patients (P=0.64). In response to endurance training, ADT-treated prostate cancer patients exhibited improved insulin sensitivity and body composition to a similar degree as eugonadal men.

Effect of endurance versus resistance training on quadriceps muscle dysfunction in COPD: a pilot study

Introduction Exercise is an important countermeasure to limb muscle dysfunction in COPD. The two major training modalities in COPD rehabilitation, endurance training (ET) and resistance training (RT), may both be efficient in improving muscle strength, exercise capacity, and health-related quality of life, but the effects on quadriceps muscle characteristics have not been thoroughly described. Methods Thirty COPD patients (forced expiratory volume in 1 second: 56% of predicted, standard deviation [SD] 14) were randomized to 8 weeks of ET or RT. Vastus lateralis muscle biopsies were obtained before and after the training intervention to assess muscle morphology and metabolic and angiogenic factors. Symptom burden, exercise capacity (6-minute walking and cycle ergometer tests), and vascular function were also assessed. Results Both training modalities improved symptom burden and exercise capacity with no difference between the two groups. The mean (SD) proportion of glycolytic type IIa muscle fibers was reduced after ET (from 48% [SD 11] to 42% [SD 10], P<0.05), whereas there was no significant change in muscle fiber distribution with RT. There was no effect of either training modality on muscle capillarization, angiogenic factors, or vascular function. After ET the muscle protein content of phosphofructokinase was reduced (P<0.05) and the citrate synthase content tended increase (P=0.08) but no change was observed after RT. Conclusion Although both ET and RT improve symptoms and exercise capacity, ET induces a more oxidative quadriceps muscle phenotype, counteracting muscle dysfunction in COPD.

Impaired Follistatin Secretion in Cirrhosis

CONTEXT Follistatin is a liver-derived inhibitor of the muscle-growth inhibitor myostatin. Reduction in acute follistatin release may help explain muscle loss in liver cirrhosis. OBJECTIVE The study aimed to investigate the capacity of acute follistatin release in patients with liver cirrhosis compared to healthy control participants. DESIGN, SETTING, AND PARTICIPANTS To experimentally increase the glucagon-insulin ratio (mimicking the hormonal effect of exercise), we infused glucagon/somatostatin (to inhibit insulin secretion) and compared the acute follistatin increase in eight male cirrhosis patients with eight healthy control participants. Patients and controls received 1-hour glucagon/somatostatin and saline infusions on 2 separate days. MAIN OUTCOME MEASURE Follistatin was measured during and 5 hours after termination of infusions. RESULTS The peak follistatin change was significantly decreased in patients with liver cirrhosis compared to healthy control participants (1.9 (interquartile range, 1.4-2.5) versus 3.6 (interquartile range, 3.0-4.0), respectively; P = .003). Patients with liver cirrhosis demonstrated significantly decreased amounts of appendicular lean mass compared to healthy controls (27.6 ± 3.8 vs 34.5 ± 2.9%, respectively; P = .001). CONCLUSIONS Patients with cirrhosis show impaired capacity to acutely secrete follistatin. The decrease in acute follistatin release may contribute to the loss of muscle mass in liver cirrhosis.

Plasma YKL-40 during pregnancy and gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is characterised by hyperglycaemia during pregnancy. The clinical circumstances involved in the development of GDM leaves the patient at a high risk of the subsequent development of type 2 diabetes. Plasma levels of the inflammation marker YKL-40 are elevated in type 2 diabetes and correlate with fasting plasma glucose levels and insulin resistance in patients with type 2 diabetes. With the present study we aimed to determine if pregnancy (and associated insulin resistance) with or without GDM affects plasma YKL-40 levels. Plasma from women diagnosed with GDM and healthy normal glucose-tolerant pregnant women (non-GDM) was obtained at the third trimester of pregnancy and again 3-4 months following delivery, and levels of YKL-40 and interleukin 6 (IL-6; known to regulate YKL-40) were measured. Plasma YKL-40 levels were similarly low during pregnancy in both groups and increased significantly after delivery, but remained lower in the GDM group compared with the non-GDM group postpartum. In contrast, plasma IL-6 levels were not affected by pregnancy or diagnosis of GDM, Nevertheless, YKL-40 levels were associated with IL-6 levels in the non-GDM group (but not in the GDM group). Pregnancy seems to be associated with a temporary reduction in circulating YKL-40, which increases after delivery, but to a much lesser extent in women with GDM than in non-GDM women.

Obesity and low-grade inflammation increase plasma follistatin-like 3 in humans.

Background. Rodent models suggest that follistatin-like 3 (fstl3) is associated with diabetes and obesity. In humans, plasma fstl3 is reduced with gestational diabetes. In vitro, TNF-α induces fstl3 secretion, which suggests a link to inflammation. Objective. To elucidate the association between plasma fstl3 and obesity, insulin resistance, and low-grade inflammation in humans. Study Design. Plasma fstl3 levels were determined in a cross-sectional study including three groups: patients with type 2 diabetes, impaired glucose tolerance, and healthy controls. In addition, lipopolysaccharide (LPS), TNF-α, or interleukin-6 (IL-6) as well as a hyperinsulinemic euglycemic clamp were used to examine if plasma fstl3 was acutely regulated in humans. Results. Plasma fstl3 was increased in obese subjects independent of glycemic state. Moreover, plasma fstl3 was positively correlated with fat mass, plasma leptin, fasting insulin, and HOMA B and negatively with HOMA S. Furthermore plasma fstl3 correlated positively with plasma TNF-α and IL-6 levels. Infusion of LPS and TNF-α, but not IL-6 and insulin, increased plasma fstl3 in humans. Conclusion. Plasma fstl3 is increased in obese subjects and associated with fat mass and low-grade inflammation. Furthermore, TNF-α increased plasma fstl3, suggesting that TNF-α is one of the inflammatory drivers of increased systemic levels of fstl3.

Comparative Effectiveness of Low-Volume Time-Efficient Resistance Training Versus Endurance Training in Patients With Heart Failure

Purpose: Cardiorespiratory fitness is positively related to heart failure (HF) prognosis, but lack of time and low energy are barriers for adherence to exercise. We, therefore, compared the effect of low-volume time-based resistance exercise training (TRE) with aerobic moderate-intensity cycling (AMC) on maximal and submaximal exercise capacity, health-related quality of life, and vascular function. Methods: Twenty-eight HF patients (New York Heart Association class I-II) performed AMC (n = 14) or TRE (n = 14). Maximal and submaximal exercise capacity, health-related quality of life, and vascular function were evaluated before and after a 6-wk training intervention with 3 training sessions per week. The AMC group and the TRE group trained for 45 and 25 min per training session, respectively. During the training sessions, the TRE and AMC groups trained at 60 ± 4% and 59 ± 2% (mean ± standard deviation) of O2peak, respectively. Results: The energy expenditure was significantly greater in AMC than in TRE (P < .05). The O2peak and Wattpeak increased in AMC group (P < .001) and TRE group (P = .001), with no differences between groups. Six-minute walk distance also increased in both groups (AMC, P = .006 and TRE, P = .036), with no difference between groups. Health-related quality of life improved equally in the 2 groups, whereas vascular function did not change in either group. Conclusion: These results demonstrate that AMC and TRE equally improved exercise capacity and health-related quality of life in lower New York Heart Association–stage HF patients, despite less time required as well as lower energy expenditure during TRE than during AMC. Therefore, TRE might represent a time-efficient exercise modality for improving adherence to exercise in patients with class I-II HF.