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Interleukin (IL)-18 is involved in regulation of lipid and glucose metabolism. Mice lacking whole-body IL-18 signalling are prone to develop weight gain and insulin resistance, a phenotype which is associated with impaired fat oxidation and ectopic skeletal muscle lipid deposition. IL-18 mRNA is expressed in human skeletal muscle but a role for IL-18 in muscle has not been identified. Patients with HIV-infection and lipodystrophy (LD) are characterized by lipid and glucose disturbances and increased levels of circulating IL-18. We hypothesized that skeletal muscle IL-18 and IL-18 receptor (R) expression would be altered in patients with HIV-lipodystrophy. Twenty-three HIV-infected patients with LD and 15 age-matched healthy controls were included in a cross-sectional study. Biopsies from the vastus lateralis muscle were obtained and IL-18 and IL-18R mRNA expression were measured by real-time PCR and sphingolipids (ceramides, sphingosine, sphingosine-1-Phosphate, sphinganine) were measured by HPLC. Insulin resistance was assessed by HOMA and the insulin response during an OGTT. Patients with HIV-LD had a 60% and 54% lower level of muscular IL-18 and IL-18R mRNA expression, respectively, compared to age-matched healthy controls. Patients with HIV-LD had a trend towards increased levels of ceramide (18.3±4.7 versus 14.8±3.0,p = 0.06) and sphingosine (0.41±0.13 versus 0.32±0.07, and lower level of sphinganine (p = 0.06). Low levels of muscle IL-18 mRNA correlated to high levels of ceramides (r = -0.31, p = 0.038) and sphingosine-1P (r = -0.29, p = 0.046) in skeletal muscle, whereas such a correlation was not found in healthy controls. Low expression of IL-18 mRNA in skeletal muscle correlated to elevated concentration of circulating triglycerides (Rp = -0.73, p<0.0001). Neither muscle expression of IL-18 mRNA or ceramide correlated to parameters of insulin resistance. IL-18 (mRNA) in skeletal muscle appears to be involved in the regulation of intramuscular lipid metabolism and hypertriglyceridemia.

Fibroblast growth factor (FGF)-21 is a novel regulator of glucose and lipid metabolism. Recently, increased FGF-21 mRNA expression in muscle was found in patients with type 2 diabetes, but the role for FGF-21 in muscle is not well understood. Patients with HIV-infection and lipodystrophy are characterised by various degree of lipid-driven insulin resistance. We hypothesized that muscle FGF-21 mRNA would be altered in HIV patients with lipodystrophy. Twenty-five HIV-infected men with lipodystrophy (LD) and 15 age-matched healthy controls, received an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp (50 mU/m2/min) combined with 6,6-H2 glucose infusion. Muscle biopsies were obtained and FGF-21 mRNA and glycogen synthase (GS) activity were measured. Subjects with HIV were insulin resistant compared with non-HIV subjects. Compared to controls, HIV subjects demonstrated a twofold increase of plasma FGF-21 from 70.4±56.8 pg/ml vs 109.1±71.8 pg/ml, respectively (p = 0.04) and an eight-fold increase in muscular FGF-21 mRNA expression (p = 0.001). Muscle FGF-21 mRNA correlated inversely with the rate of disappearance of glucose during insulin clamp (r = -0.54, p = 0.0009), and the GS fractional velocity in muscle (r = -0.39, p = 0.03), and directly with fasting insulin (r = 0.50, p = 0.0022), HOMA-IR (r = 0.47, p = 0.004), triglycerides (r = 0.60. P = 0.0001), waist-to-hip ratio (r = 0.51, p = 0.0001) and limb fat mass (-0.46, p = 0.004), but not to plasma FGF-21. FGF-21 mRNA is increased in skeletal muscle in HIV patients and correlates to whole-body (primarily reflecting muscle) insulin resistance, but not to plasma FGF-21. Those findings add to the evidence that FGF-21 is a myokine and may suggest that muscle FGF-21 is working in a local manner.

[This corrects the article DOI: 10.1371/journal.pone.0186755.].

Aim Physical activity after prostate cancer diagnosis has been shown to reduce the risk of disease progression. Here, we aimed to evaluate the effect of a 2-year home-based endurance training intervention on body composition, biomarkers levels, and prostate-specific antigen (PSA) doubling time as a surrogate end-point for progressing disease. Methods Out-clinic patients with either biochemical recurrence following radical prostatectomy or patients managed on active surveillance were randomized to either 24 months (3 times/week) of home-based endurance training or usual care. Aerobic fitness, body composition, insulin sensitivity, and biomarkers were measured at 0, 6, and 24 months of intervention. PSA doubling time (PSADT) was calculated based on monthly PSA measurements. Results Twenty-five patients were enrolled, and 19 patients completed the study. PSADT increased in the training group from 28 to 76 months ( p  < 0.05) during the first 6 months and was correlated with changes in VO 2 max ( p  < 0.01, r 2  = 0.41). The training group lost 3.6 ± 1.0 kg ( p  < 0.05) exclusively as fat mass, yet the changes in body composition were not associated with the increased PSADT. The training group showed significant improvements in plasma triglycerides, adiponectin, IGF-1, IGFBP-1, and fasting glucose levels, but no changes in insulin sensitivity (measured as Matsuda index), testosterone, cholesterols, fasting insulin, plasma TNF-alpha, IL-6, or leptin levels. The control group showed no changes in any of the evaluated parameters across the 2-year intervention. Conclusion In this small randomized controlled trial, we found that improvements in fitness levels correlated with increasing PSADT, suggesting a link between training and disease progression.

Human immunodeficiency virus (HIV)‐infected patients with lipodystrophy have decreased insulin‐stimulated glucose uptake. Both endurance and resistance training improve insulin‐stimulated glucose uptake in skeletal muscle of HIV‐infected patients, but the mechanisms are unknown. This study aims to identify the molecular pathways involved in the beneficial effects of training on insulin‐stimulated glucose uptake in skeletal muscle of HIV‐infected patients. Eighteen sedentary male HIV‐infected patients underwent a 16 week supervised training intervention, either resistance or strength training. Euglycemic–hyperinsulinemic clamps with muscle biopsies were performed before and after the training interventions. Fifteen age‐ and body mass index (BMI)‐matched HIV‐negative men served as a sedentary baseline group. Phosphorylation and total protein expression of insulin signaling molecules as well as glycogen synthase (GS) activity were analyzed in skeletal muscle biopsies in relation to insulin stimulation before and after training. HIV‐infected patients had reduced basal and insulin‐stimulated GS activity (%fractional velocity, [FV]) as well as impaired insulin‐stimulated Aktthr308 phosphorylation. Despite improving insulin‐stimulated glucose uptake, neither endurance nor strength training changed the phosphorylation status of insulin signaling proteins or affected GS activity. However; endurance training markedly increased the total Akt protein expression, and both training modalities increased hexokinase II (HKII) protein. HIV‐infected patients with lipodystrophy have decreased insulin‐stimulated glucose uptake in skeletal muscle and defects in insulin‐stimulated phosphorylation of Aktthr308. Endurance and strength training increase insulin‐stimulated glucose uptake in these patients, and the muscular training adaptation is associated with improved capacity for phosphorylation of glucose by HKII, rather than changes in markers of insulin signaling to glucose uptake or glycogen synthesis. e00060 Human immunodeficiency virus (HIV)‐infected patients with lipodystrophy have decreased insulin‐stimulated glucose uptake in skeletal muscle and defects in insulin‐stimulated phosphorylation of Aktthr308. Endurance and strength training increase insulin‐stimulated glucose uptake in these patients, and the muscular training adaptation is associated with improved capacity for phosphorylation of glucose by HKII, rather than changes in markers of insulin signaling to glucose uptake or glycogen synthesis.