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New Findings What is the central question of this study? A positive association between telomere length and exercise training has been shown in cardiac tissue of mice. It is currently unknown how each bout of exercise influences telomere-length-regulating proteins. We sought to determine how a bout of exercise altered the expression of telomere-length-regulating genes and a related signalling pathway in cardiac tissue of mice., What is the main finding and its importance? Acute exercise altered the expression of telomere-length-regulating genes in cardiac tissue and might be related to altered mitogen-activated protein kinase signalling. These findings are important in understanding how exercise provides a cardioprotective phenotype with ageing., Age is the greatest risk factor for cardiovascular disease. Telomere length is shorter in the hearts of aged mice compared with young mice, and short telomere length has been associated with an increased risk of cardiovascular disease. One year of voluntary wheel-running exercise attenuates the age-associated loss of telomere length and results in altered gene expression of telomere-length-maintaining and genome-stabilizing proteins in heart tissue of mice. Understanding the early adaptive response of the heart to an endurance exercise bout is paramount to understanding the impact of endurance exercise on heart tissue and cells. To this end, we studied mice before (BL), immediately after (TP1) and 1 h after a treadmill running bout (TP2). We measured the changes in expression of telomere-related genes (shelterin components), DNA-damage-sensing ( p53 and Chk2) and DNA-repair genes ( Ku70 and Ku80) and mitogen-activated protein kinase (MAPK) signalling. The TP1 animals had increased TRF1 and TRF2 protein and mRNA levels, greater expression of DNA-repair and -response genes ( Chk2 and Ku80) and greater protein content of phosphorylated p38 MAPK compared with both BL and TP2 animals. These data provide insights into how physiological stressors remodel the heart tissue and how an early adaptive response mediated by exercise may be maintaining telomere length and/or stabilizing the heart genome through the upregulation of telomere-protective genes. [ABSTRACT FROM AUTHOR]

New findings What is the central question of this study? How does parental exercise training directly and/or transgenerationally affect offspring phenotypes over two generations of mice?, What is the main finding and what is its importance? We observed preliminary evidence that parental exercise training can influence health-related phenotypes (e.g. body and fat mass, muscle gene expression) in mouse offspring. These findings indicate that parental exercise may be another environmental factor (like altered nutrition) capable of influencing offspring phenotypes in adulthood., Early life and preconception environmental stimuli can affect adult health-related phenotypes. Exercise training is an environmental stimulus affecting many systems throughout the body and appears to alter offspring phenotypes. The aim of this study was to examine the influence of parental exercise training, or 'exercise ancestry', on morphological and metabolic phenotypes in two generations of mouse offspring. The F0 C57BL/6 mice were exposed to voluntary exercise (EX) or sedentary lifestyle (SED) and bred with like-exposed mates to produce an F1 generation. The F1 mice of both ancestries were sedentary and killed at 8 weeks or bred with littermates to produce an F2 generation, which was also sedentary and killed at 8 weeks. Small but broad generation- and sex-specific effects of exercise ancestry were observed for body mass, fat and muscle mass, serum insulin, glucose tolerance and muscle gene expression. The F1 EX females were lighter than F1 SED females and had lower absolute tibialis anterior and omental fat masses. Serum insulin was higher in F1 EX females compared with F1 SED females. The F2 EX females had impaired glucose tolerance compared with F2 SED females. Analysis of skeletal muscle mRNA levels revealed several generation- and sex-specific differences in mRNA levels for multiple genes, especially those related to metabolic genes (e.g. F1 EX males had lower mRNA levels of Hk2, Ppard, Ppargc1a, Adipoq and Scd1 than F1 SED males). These results provide preliminary evidence that parental exercise training can influence health-related phenotypes in mouse offspring. [ABSTRACT FROM AUTHOR]

Acute exercise and exercise training may influence putative endothelial progenitor cell (EPC) number and colony forming units (CFU-ECs), although the mechanisms remain unclear. This study examined the effects of in vitro thrombin supplementation and acute exercise on CFU-EC gene expression, associated with cellular proliferation and differentiation. The effect of habitual physical activity was evaluated through analysis of EPCs from chronically high- and low-active men. Participants were healthy high- and low-active men (n = 23), aged 55-80 yr. Circulating CD34+/VEGFR2+ number, CFU-ECs, plasma prothrombin fragment (FI +2), and thrombin-antithrombin III were measured at rest and after 30 rain of exercise. Gene expression of cyclin A2, cyclin D1, p27, VE-cadherin, and VEGFR2 was assessed in postexercise CFU-ECs and resting CFU-ECs treated with 0, 1, 5, or 10 U/ml of thrombin. Outcomes were compared between high- and low-active participants. FI +2 and thmmbin-antithrombin III, but not CD34+/VEGFR2+ number and CFU-ECs, increased with exercise. Exercise-induced changes in FI +2 correlated with changes in CD34+/VEGFR2+ number in both groups. Thrombin treatments and acute exercise increased cyclin A2 and cyclin D1 expression and decreased p27 expression. One unit per milliliter thrombin increased VEGFR2 and VE-cadherin expression, whereas 5 U/ml, 10 U/ml, and acute exercise did not elicit any changes. An exercise training effect was observed with greater decreases in p27 expression with 5 and 10 U/ml thrombin and greater increases in VEGFR2 and VE-cadherin expression with I U/ml thrombin in high-active men. Exercise-induced changes in putative EPC gene expression are associated with thrombin production and may be modulated by long-term exercise training. [ABSTRACT FROM AUTHOR]

Suppressor of cytokine signalling-3 (SOCS-3) has been implicated in the onset of insulin resistance in non-muscle tissue. Thus, we examined the effects of exercise training on SOCS-3 expression and the potential role of SOCS-3 in muscle. Female Sprague-Dawley rats (5–8 months) were treadmill trained for 12 weeks and the muscles were removed 24 h after the last bout of exercise. Exercise training increased SOCS-3 mRNA expression by 80% and 154% in the plantaris and soleus muscle, respectively. To mimic the effects of increased SOCS-3 expression, SOCS-3 cDNA was cotransfected with a NF-kappa B ( NF-κB) luciferase construct into cultured C2C12 myotubes. SOCS-3 overexpression increased NF-κB transcriptional activity by 27-fold. The proximal region of the IL-6 gene promoter contains a NF-κB consensus site, which contributes to increased IL-6 expression in various tissues. SOCS-3 cDNA was cotransfected into cultured C2C12 myotubes with either the IL-6 luciferase construct or a mutated NF-κB IL-6 luciferase construct. SOCS-3 overexpression increased IL-6 transcriptional activity by 15-fold, however, when the NF-κB site was mutated SOCS-3 failed to increase IL-6 transcriptional activity. We subsequently found that IL-6 mRNA expression was elevated in the plantaris and soleus muscles of the trained animals compared to the sedentary animals. Finally, exercise induced a significant reduction in IκBα and increased phosphorylation of Iκκ suggesting that NF-κB activation was elevated after exercise training. These data suggest that training-induced elevations in SOCS-3 expression in skeletal muscle may contribute to the exercise-induced increase in IL-6 expression through alterations in the mechanisms that mediate NF-κB activity. [ABSTRACT FROM AUTHOR]

Myoblast differentiation is characterized by a sequence of events that includes an increase in insulin-like growth factor (IGF)-I and contractile gene expression. The increase in IGF-I expression activates cell signaling mechanisms that participate in the differentiation process. One potential contributor is the SOCS-3 (suppressor of cytokine signaling-3) gene, which regulates signaling mechanisms and may be sensitive to changes in IGF-I concentrations. For the first time, the role of SOCS-3 is investigated in myoblast differentiation. SOCS-3 mRNA levels and SOCS-3 transcriptional activity increase during myoblast differentiation. SOCS-3 gene expression is induced, at least in part, by activation of the IGF-I receptor during myoblast differentiation. Overexpression of SOCS-3 cDNA significantly increased transcriptional activation of the 2.0-kb skeletal α-actin promoter in differentiating C2C12 myoblasts. In addition, overexpression of SOCS-3 specifically increased serum response factor-driven transcriptional activity but had no effect on nuclear-factor of activated T cell-driven transcriptional activity. SOCS-3 overexpression induced skeletal α-actin transcription in a myoblast cell line that cannot respond to endogenous IGF-I, indicating that SOCS-3 can contribute to the myoblast differentiation process in the absence of IGF-I. These data suggest that IGF-I induces myoblast differentiation, in part, by increasing SOCS-3 expression. [ABSTRACT FROM AUTHOR]

Aged individuals suffer from multiple dysfunctions during skeletal muscle atrophy. The purpose of this study was to determine differential changes in gene expression in atrophied soleus muscle induced by hindlimb immobilization in young (3-4 months) and old (30-31 months) rats. The hypothesis was that differentially expressed mRNAs with age--atrophy interactions would reveal candidates that induce loss of function responses in aged animals. Each muscle was applied to an independent set of Affymetrix micoarrays, with 385 differentially expressed mRNAs with atrophy and 354 age--atrophy interactions detected by two-factor ANOVA (α of 0.05 with a Bonferroni adjustment). Functional trends were observed for 23 and 15 probe sets involved in electron transport and the extracellular matrix, respectively, decreasing more in the young than in the old. Other functional categories with atrophy in both ages included chaperones, glutathione-Stransferases, the tricarboxylic acid cycle, reductions in Z-line-associated proteins and increases in probe sets for protein degradation. Surprisingly, myosin heavy chain IIb and IIx mRNAs were suppressed in the atrophied soleus muscle of old rats as opposed to the large increases in the young animals (16- and 25-fold, respectively, with microarrays, and 61- and 68-fold, respectively, with real-time PCR). No significant changes were observed in myosin heavy chain IIb and IIx mRNA with micoarrays in the atrophied soleus muscles of old rats, but they were found to increase six- and fivefold, respectively, with real-time PCR. Therefore, deficiencies in pre-translational signals that normally upregulate myosin heavy chain IIb and IIx mRNAs during atrophy may exist in the soleus muscle of old animals. [ABSTRACT FROM AUTHOR]

The purpose of the current study was to examine IGFBP-3, -4, and -5 mRNA and protein expression levels as a function of muscle type, age, and regrowth from an immobilization-induced atrophy in Fischer 344 × Brown Norway rats. IGFBP-3 mRNA expression in the 4-mo-old animals was significantly higher in the red and white portions of the gastrocnemius muscle compared with the soleus muscle. However, there were no significant differences in IGFBP-3 mRNA expression among any of the muscle groups in the 30-mo-old animals. There were no significant differences in IGFBP-5 mRNA expression in any of the muscle groups, whereas in the 30-mo-old animals there was significantly less IGFBP-5 mRNA expression in the white gastrocnemius compared with the red gastrocnemius muscles. Although IGFBP-3 and -5 proteins were detected in the type I soleus muscle with Western blot analyses, no detection was observed in the type II red and white portions of the gastrocnemius muscle. Aging from adult (18 mo) to old animals (30 mo) was associated with decreases in IGFBP-3 mRNA and protein and IGFBP-5 protein only in the soleus muscle. After 10 days of recovery from 10 days of hindlimb immobilization, IGFBP-3 mRNA and protein increased in soleus muscles from young (4-mo) rats; however, only IGFBP-3 protein increased in the old (30-mo) rats. Whereas there were no changes in IGFBP-5 mRNA expression during recovery, IGFBP-5 protein in the 10-day-recovery soleus muscle did increase in the young, but not in the old, rats. Because one of the functions of IGFBPs is to modulate IGF-I action on muscle size and phenotype, it is hypothesized that IGFBP-3 and -5 proteins may have potential modulatory roles in type I fiber-dominated muscles, aging, and regrowth from atrophy. [ABSTRACT FROM AUTHOR]

To determine the role of the IGF-I receptor in skeletal muscle hypertrophy, we utilized a transgenic mouse model that expresses a dominant negative IGF-I receptor specifically in skeletal muscle (MKR). Muscle hypertrophy was induced by using the functional overload model (FO) of the plantaris muscle. This model results in significant elevations of IGF-I expression in skeletal muscle. Adult male wild type (WT) and MKR mice were subjected to non-FO, 7 or 35 days of FO. In the non-FO animals, plantaris mass was 11% (p<0.05) greater in WT compared to MKR mice. After 7 days of FO, plantaris mass significantly increased by 37 and 48 % in WT and MKR mice, respectively. After 35 days of FO, the WT and MKR mice demonstrated significant increases in plantaris mass of 98% and 122%, respectively. However, at no time point after the FO were significant differences detected in plantaris mass between the WT and MKR mice. Previous research suggests that IGF-I-induces muscle growth through activation of the Akt-mTOR signaling pathway. Therefore, we measured the phosphorylation status of Akt and p70s6k in the WT and MKR mice after 7 days of FO. There were significant increases in Akt (Ser-473) and p70s6k (Thr-389) phosphorylation in both the WT and MKR mice when compared to the non-FO WT and MKR mice. However, no significant differences were detected in phosphorylation between the WT and MKR mice at 7 days if FO. These data suggest that increased mechanical load can induce muscle growth and activate Akt and p70s6k independent of a functioning IGF-I receptor. [ABSTRACT FROM AUTHOR]