IL-15 improves skeletal muscle oxidative metabolism and glucose uptake in association with increased respiratory chain supercomplex formation and AMPK pathway activation.

BACKGROUND: IL-15 is believed to play a role in the beneficial impact of exercise on muscle energy metabolism. However, previous studies have generally used supraphysiological levels of IL-15 that do not represent contraction-induced IL-15 secretion. METHODS: L6 myotubes were treated acutely (3 h) and chronically (48 h) with concentrations of IL-15 mimicking circulating (1-10 pg/ml) and muscle interstitial (100 pg/ml -20 ng/ml) IL-15 levels with the aim to better understand its autocrine/paracrine role on muscle glucose uptake and mitochondrial function. RESULTS: Acute exposure to IL-15 levels representing muscle interstitial IL-15 increased basal glucose uptake without affecting insulin sensitivity. This was accompanied by increased mitochondrial oxidative functions in association with increased AMPK pathway and formation of complex III-containing supercomplexes. Conversely, chronic IL-15 exposure resulted in a biphasic effect on mitochondrial oxidative functions and ETC supercomplex formation was increased with low IL-15 levels but decreased with higher IL-15 concentrations. The AMPK pathway was activated only by high levels of chronic IL-15 treatment. Similar results were obtained in skeletal muscle from muscle-specific IL-15 overexpressing mice that show very high circulating IL-15 levels. CONCLUSIONS: Acute IL-15 treatment that mimics local IL-15 concentrations enhances muscle glucose uptake and mitochondrial oxidative functions. That mitochondria respond differently to different levels of IL-15 during chronic treatments indicates that IL-15 might activate two different pathways in muscle depending on IL-15 concentrations. GENERAL SIGNIFICANCE: Our results suggest that IL-15 may act in an autocrine/paracrine fashion and be, at least in part, involved in the positive effect of exercise on muscle energy metabolism.

Resistance exercise training modulates acute gene expression during human skeletal muscle hypertrophy.

We sought to determine whether acute resistance exercise (RE)-induced gene expression is modified by RE training. We studied the expression patterns of a select group of genes following an acute bout of RE in naïve and hypertrophying muscle. Thirteen untrained subjects underwent supervised RE training for 12 wk of the nondominant arm and performed an acute bout of RE 1 wk after the last bout of the training program (training+acute). The dominant arm was either unexercised (control) or subjected to the same acute exercise bout as the trained arm (acute RE). Following training, men (14.8 ± 2.8%; P < 0.05) and women (12.6 ± 2.4%; P < 0.05) underwent muscle hypertrophy with increases in dynamic strength in the trained arm (48.2 ± 5.4% and 72.1 ± 9.1%, respectively; P < 0.01). RE training resulted in attenuated anabolic signaling as reflected by a reduction in rpS6 phosphorylation following acute RE. Changes in mRNA levels of genes involved in hypertrophic growth, protein degradation, angiogenesis, and metabolism commonly expressed in both men and women was determined 4 h following acute RE. We show that RE training can modify acute RE-induced gene expression in a divergent and gene-specific manner even in genes belonging to the same ontology. Changes in gene expression following acute RE are multidimensional, and may not necessarily reflect the actual adaptive response taking place during the training process. Thus RE training can selectively modify the acute response to RE, thereby challenging the use of gene expression as a marker of exercise-induced adaptations.

Adiposity attenuates muscle quality and the adaptive response to resistance exercise in non-obese, healthy adults.

BACKGROUND: Emerging data have revealed a negative association between adiposity and muscle quality (MQ). There is a lack of research to examine this interaction among young, healthy individuals, and to evaluate the contribution of adiposity to adaptation after resistance exercise (RE). OBJECTIVE: The purpose of this investigation was to examine the influence of subcutaneous adipose tissue (SAT) on muscle function among non-obese individuals before and after RE. DESIGN: Analyses included 634 non-obese (body mass index <30 kg m(-2)) subjects (253 males, 381 females; age=23.3 ± 5.2 years). SAT and muscle mass (magnetic resonance imaging-derived SAT and biceps muscle volume), isometric and dynamic biceps strength, and MQ (strength/muscle volume), were analyzed at baseline and after 12 weeks of unilateral RE. RESULTS: At baseline, SAT was independently associated with lower MQ for males (ß=-0.55; P<0.01) and females (ß=-0.45; P<0.01), controlling for body mass and age. Adaptation to RE revealed a significant negative association between SAT and changes for strength capacity (ß=-0.13; p=0.03) and MQ (ß=-0.14; P<0.01) among males. No attenuation was identified among females. Post-intervention SAT remained a negative predictor of MQ for males and females (ß=-0.47; P<0.01). CONCLUSIONS: The findings reveal that SAT is a negative predictor of MQ among non-obese, healthy adults, and that after 12 weeks of progressive RE this association was not ameliorated. Data suggest that SAT exerts a weak, negative influence on the adaptive response to strength and MQ among males.

The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity.

BACKGROUND: Myostatin, also known as Growth and Differentiation Factor 8, is a secreted protein that inhibits muscle growth. Disruption of myostatin signaling increases muscle mass and decreases glucose, but it is unclear whether these changes are related. We treated mice on chow and high-fat diets with a soluble activin receptor type IIB (ActRIIB, RAP-031), which is a putative endogenous signaling receptor for myostatin and other ligands of the TGF-beta superfamily. RESULTS: After 4 weeks, RAP-031 increased lean and muscle mass, grip strength and contractile force. RAP-031 enhanced the ability of insulin to suppress glucose production under clamp conditions in high-fat fed mice, but did not significantly change insulin-mediated glucose disposal. The hepatic insulin-sensitizing effect of RAP-031 treatment was associated with increased adiponectin levels. RAP-031 treatment for 10 weeks further increased muscle mass and drastically reduced fat content in mice on either chow or high-fat diet. RAP-031 suppressed hepatic glucose production and increased peripheral glucose uptake in chow-fed mice. In contrast, RAP-031 suppressed glucose production with no apparent change in glucose disposal in high-fat-diet mice. CONCLUSION: Our findings show that disruption of ActRIIB signaling is a viable pharmacological approach for treating obesity and diabetes.

Influence of carbohydrate and age on lymphocyte function following a marathon.

The influence of 6% carbohydrate ingestion and age on PHA-induced lymphocyte proliferation and in vitro cytokine production was studied in 48 runners following a competitive marathon. Runners were randomly assigned to carbohydrate (C; n = 23) and placebo (P; n= 25) groups, with blood samples taken before, immediately after, and 1.5 hr post-race. C versus P ingestion resulted in higher plasma glucose, lower plasma cortisol, reduced neutrophilia, and monocytosis during recovery, but had no effect on the post-exercise reduction in T-lymphocytes or NK cells, or on race times. No group differences were observed for PHA-induced lymphocyte proliferation or cytokine production. However, for all subjects combined, lymphocyte proliferation and IFN-gamma secretion decreased significantly below pre-race values by 1.5 hr of recovery, and these were negatively correlated with plasma cortisol. Young (<50 years; n = 36) and old (>or=50 years; n = 12) runners exhibited parallel post-race declines in lymphocyte proliferation and IFN-gamma secretion, with the older group exhibiting a 33-59% lower proliferation at each time point. In conclusion, PHA-induced lymphocyte proliferation and cytokine production decreased significantly following a marathon, and this decrease was strongly linked to cortisol and only partially linked to T-cell changes. This decrease occurred in both younger and older runners and was not influenced by carbohydrate.

Hysteroscopic diagnosis of uterine intracavitary disorders.

The fundamental role of hysteroscopy in the diagnosis of intracavitary disorders in gynecology and in particular in female sterility and infertility, is stressed. The outcomes of a 12-year experience with hysteroscopy, are reported. Its indications, contraindications and side-effects in a group of 7327 patients undergoing hysteroscopy, are discussed. In this patient population, sterility and infertility were the second most common indication for hysteroscopy after abnormal uterine bleeding. The role of malformations such as uterus septus and subseptus, inflammation with hysteroscopic findings of uterine synechiae and focal lesions as polyps and myomas was examined. Particular attention was paid to the study of tubal ostia and endometrial morphology in relation to the phase of menstrual cycle. In a smaller group of infertile patients, hysteroscopy was compared with hysterosalpingography, stressing the sensitivity and specificity of the latter as compared to the former.

A comparison of hysteroscopy and hysterosalpingography.

OBJECTIVE: The aim of this study was to assess the diagnostic reliability of hysteroscopy (HSC) and hysterosalpingography (HSG) in patients suffering from primary and secondary infertility. METHOD: Seventy women (50 with primary and 20 with secondary infertility) undergoing HSC and HSG were prospectively studied and the diagnostic capacity of the two techniques was compared. RESULTS: HSG proved to have a sensitivity of 79.1% and a specificity of 81.8%, with an 18.1% false-positive rate and a 18.9% false-negative rate. CONCLUSION: HSG is of exclusive importance in the assessment of tubal morphology and function and has a secondary and complementary role to HSC in the inspection of the uterine cavity and tubal ostia.

Ovarian sensitivity to follicle-stimulating hormone during the follicular phase of the human menstrual cycle and in patients with polycystic ovarian syndrome.

OBJECTIVE: To investigate the existence of a different sensitivity of ovaries to follicle-stimulating hormone (FSH) during the follicular phase of the human menstrual cycle and in patients with polycystic ovarian syndrome (PCOS). DESIGN: Thirty-four normal subjects and 13 patients with PCOS were treated intravenously by FSH (75 or 225 IU) or saline at different stages of follicular phase. MAIN OUTCOME MEASURES: Plasma levels of luteinizing hormone (LH), FSH, estradiol (E2), and testosterone (T) in samples collected for a period of 26 hours after the injection. RESULTS: In patients at the early stages of follicular phase (baseline E2 < 50 pg/mL), FSH increased in dose-dependent manner E2 and E2:T-stimulated area under curve (AUC) in respect to saline experiments. In PCOS subjects, saline E2, and E2:T-stimulated AUC were significantly lower than normal women. Follicle-stimulating hormone (75 IU) dramatically increased these values, and no difference was seen in respect to 75 and 225 IU FSH-treated controls. In patients with E2 baseline plasma levels > 50 pg/mL, FSH (75 or 225 IU) failed to increase both E2 and E2:T-stimulated AUC in comparison with saline studies. CONCLUSIONS: Early stages of follicular phase in normal and polycystic ovaries are the most responsive to the elevation of circulating FSH levels, whereas the ovarian sensitivity spontaneously decreases as follicular maturation enhances.