Andrew T. Ludlow

Relationship between Physical Activity Level, Telomere Length, and Telomerase Activity

PURPOSE The purpose of this study was to examine the relationship of exercise energy expenditure (EEE) with both telomere length and telomerase activity in addition to accounting for hTERT C-1327T promoter genotype. METHODS Sixty-nine (n = 34 males; n = 35 females) participants 50-70 yr were assessed for weekly EEE level using the Yale Physical Activity Survey. Lifetime consistency of EEE was also determined. Subjects were recruited across a large range of EEE levels and separated into quartiles: 0-990, 991-2340, 2341-3540, and >3541 kcal x wk(-1). Relative telomere length and telomerase activity were measured in peripheral blood mononuclear cells (PBMC). RESULTS The second EEE quartile exhibited significantly longer telomere lengths [1.12 +/- 0.03 relative units (RU)] than both the first and fourth EEE quartiles (0.94 +/- 0.03 and 0.96 +/- 0.03 RU, respectively; P < 0.05) but was not different from the third quartile. Telomerase activity was not different among the EEE quartiles. An association was observed between telomerase enzyme activity and hTERT genotype with the TT genotype (1.0 x 10(-2) +/- 4.0 x 10(-3) attomoles (amol) per 10,000 cells; n = 19) having significantly greater telomerase enzyme activity than both the CT (1.3 x 10(-3) +/- 3.2 x 10(-3); n = 30) and CC groups (5.0 x 10(-4) +/- 3.9 x 10(-3); n = 20; P = 0.01). CONCLUSION These results indicate that moderate physical activity levels may provide a protective effect on PBMC telomere length compared with both low and high EEE levels.

ACE Genotype and the Muscle Hypertrophic and Strength Responses to Strength Training

PURPOSE Previous studies have linked an insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene with variability in muscle strength responses to strength training (ST), though conclusions have been inconsistent across investigations. Moreover, most previous studies have not investigated the influence of sex on the association of ACE I/D genotype with muscle phenotypes. The purpose of this study was to investigate the association of ACE genotype with muscle phenotypes before and after ST in older men and women. METHODS Eighty-six inactive men and 139 inactive women, ages 50-85 yr (mean: 62 yr), were studied before and after 10 wk of unilateral knee extensor ST. The one-repetition maximum (1RM) test was used to assess knee extensor muscle strength, and computed tomography was used to measure quadriceps muscle volume (MV). Differences were compared among ACE genotype groups (II vs ID vs DD). RESULTS Across the entire cohort at baseline, ACE genotype was significantly associated with total lean mass and body weight, with higher values in DD genotype carriers (both P < 0.05). At baseline, DD genotype carriers exhibited significantly greater MV compared with II genotype carriers for both the trained leg (men: 1828 +/- 44 vs 1629 +/- 70; women: 1299 +/- 34 vs 1233 +/- 49; P = 0.02) and untrained leg (men: 1801 +/- 46 vs 1559 +/- 72; women: 1268 +/- 36 vs 1189 +/- 51; P = 0.01), with no significant genotype x sex interaction. No ACE genotype associations were observed for the 1RM or MV adaptations to ST in either men or women. CONCLUSIONS In the present study, ACE genotype was associated with baseline differences in muscle volume, but it was not associated with the muscle hypertrophic response to ST.

Exercise, APOE, and working memory: MEG and behavioral evidence for benefit of exercise in epsilon4 carriers.

Performance on the Sternberg working memory task, and MEG cortical response on a variation of the Sternberg task were examined in middle-aged carriers and non-carriers of the APOE epsilon4 allele. Physical activity was also assessed to examine whether exercise level modifies the relationship between APOE genotype and neurocognitive function. Regression revealed that high physical activity was associated with faster RT in the six- and eight-letter conditions of the Sternberg in epsilon4 carriers, but not in the non-carriers after controlling for age, gender, and education (N=54). Furthermore, the MEG analysis revealed that sedentary epsilon4 carriers exhibited lower right temporal lobe activation on matching probe trials relative to high-active epsilon4 carriers, while physical activity did not distinguish non-carriers (N=23). The M170 peak was identified as a potential marker for pre-clinical decline as epsilon4 carriers exhibited longer M170 latency, and highly physically active participants exhibited greater M170 amplitude to matching probe trials.

Physical Activity and Telomere Biology: Exploring the Link with Aging-Related Disease Prevention

Physical activity is associated with reduced risk of several age-related diseases as well as with increased longevity in both rodents and humans. Though these associations are well established, evidence of the molecular and cellular factors associated with reduced disease risk and increased longevity resulting from physical activity is sparse. A long-standing hypothesis of aging is the telomere hypothesis: as a cell divides, telomeres shorten resulting eventually in replicative senescence and an aged phenotype. Several reports have recently associated telomeres and telomere-related proteins to diseases associated with physical inactivity and aging including cardiovascular disease, insulin resistance, and hypertension. Interestingly several reports have also shown that longer telomeres are associated with higher physical activity levels, indicating a potential mechanistic link between physical activity, reduced age-related disease risk, and longevity. The primary purpose of this review is to discuss the potential importance of physical activity in telomere biology in the context of inactivity- and age-related diseases. A secondary purpose is to explore potential mechanisms and important avenues for future research in the field of telomeres and diseases associated with physical inactivity and aging.

Do Telomeres Adapt to Physiological Stress? Exploring the Effect of Exercise on Telomere Length and Telomere-Related Proteins

Aging is associated with a tissue degeneration phenotype marked by a loss of tissue regenerative capacity. Regenerative capacity is dictated by environmental and genetic factors that govern the balance between damage and repair. The age-associated changes in the ability of tissues to replace lost or damaged cells is partly the cause of many age-related diseases such as Alzheimers disease, cardiovascular disease, type II diabetes, and sarcopenia. A well-established marker of the aging process is the length of the protective cap at the ends of chromosomes, called telomeres. Telomeres shorten with each cell division and with increasing chronological age and short telomeres have been associated with a range of age-related diseases. Several studies have shown that chronic exposure to exercise (i.e., exercise training) is associated with telomere length maintenance; however, recent evidence points out several controversial issues concerning tissue-specific telomere length responses. The goals of the review are to familiarize the reader with the current telomere dogma, review the literature exploring the interactions of exercise with telomere phenotypes, discuss the mechanistic research relating telomere dynamics to exercise stimuli, and finally propose future directions for work related to telomeres and physiological stress.

Telomeres Shorten in Response to Oxidative Stress in Mouse Skeletal Muscle Fibers

Aging phenotypes are dictated by myriad cellular changes including telomere shortening. In most tissues, telomere shortening is accelerated during replication if unrepaired oxidative damage to telomere sequences is present. However, the effect of reactive oxygen species exposure on skeletal muscle telomeres is unknown. We sought to determine if oxidative stress shortens telomeres in isolated adult rodent skeletal muscle fibers. Flexor digitorum brevis muscles were dissected from male mice (C57BL/6, long telomere and CAST/Ei, wild-derived, short telomere) and dissociated into single fibers. Fibers were cultured at an oxygen tension of 2%-5% for 5 days in control, hydrogen peroxide (oxidant), or a combination of N-acetylcysteine (antioxidant) and oxidant containing media. Telomere length, telomerase enzyme activity, and protein content of TRF1 and TRF2 were subsequently measured. In both strains, oxidative stress resulted in significant telomere shortening in isolated skeletal muscle fibers, likely by different mechanisms. Telomerase activity was not altered by oxidative stress treatment but was significantly different between strains, with greater telomerase activity in long-telomere-bearing C57BL/6 mice. These results provide important insights into mechanisms by which oxidative stress could shorten skeletal muscle telomeres.

Chronic Exercise Modifies Age-Related Telomere Dynamics in a Tissue-Specific Fashion

We evaluated the impact of long-term exercise on telomere dynamics in wild-derived short telomere mice (CAST/Ei) over 1 year. We observed significant telomere shortening in liver and cardiac tissues in sedentary 1-year-old mice compared with young (8 weeks) baseline mice that were attenuated in exercised 1-year-old animals. In contrast, skeletal muscle exhibited significant telomere shortening in exercise mice compared with sedentary and young mice. Telomerase enzyme activity was increased in skeletal muscle of exercise compared with sedentary animals but was similar in cardiac and liver tissues. We observed significant age-related decreases in expression of telomere-related genes that were attenuated by exercise in cardiac and skeletal muscle but not liver. Protein content of TRF1 was significantly increased in plantaris muscle with age. In summary, long-term exercise altered telomere dynamics, slowing age-related decreases in telomere length in cardiac and liver tissue but contributing to shortening in exercised skeletal muscle.

ACTN3 Genotype Does not Influence Muscle Power

The R577X polymorphism within the ACTN3 gene has been associated with elite athletic performance, strength, power, fat free mass, and adaptations to strength training, though inconsistencies exist in the literature. The specific muscle power phenotypes most influenced by the polymorphism are uncertain. The purpose of this study was to examine the association between ACTN3 R577X genotype and muscle power phenotypes. Recreationally active young men and women (N=57) were selected to complete 2 muscle performance assessments, an isokinetic fatigue protocol at testing speeds of 180°  s (-1) and 250°  s (-1) and a 30 s Wingate test. Isokinetic torque and Wingate power significantly decreased over the duration of each test, but no differences in the rate of decline were observed among ACTN3 genotype groups. Similarly, no significant genotype differences were observed for isokinetic peak torque, Wingate absolute or relative peak power, or fatigue index. These results indicate that in recreationally active individuals the ACTN3 R577X polymorphism is not associated with muscle performance phenotypes, supporting recent findings that R577X may only be important for predicting performance in elite athletes. Our data also indicate that using this polymorphism for genetic screening in the lay population is scientifically questionable.

Sex‐specific effects of exercise ancestry on metabolic, morphological and gene expression phenotypes in multiple generations of mouse offspring

•  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.

Exercise alters mRNA expression of telomere-repeat binding factor 1 in skeletal muscle via p38 MAPK

Telomeres protect chromosome ends and shorten with age in most tissues. Integral to the maintenance of telomeres is the protein complex shelterin. The gene expression regulation of shelterin proteins to physiological stressors is not understood in vivo. We have recently reported increased telomere-repeat binding factor 1 (TRF1) protein expression and longer telomere length in skeletal muscle of sedentary compared with chronically active mice. These provocative observations led us to examine the effects of acute physiological stress on shelterin expression in vivo in mice and to further define potential mechanisms associated with gene regulation of shelterin. Three groups of female C57Bl/6 mice were studied: one control group and two groups that underwent a 30-min treadmill running bout and were killed either immediately following or 1-h after the exercise. Following the exercise bout, mRNA expression of Trf1 was significantly reduced in the plantaris muscle, and this reduction was paralleled by significant increases in p38 MAPK phosphorylation. To determine if p38 mediated the decreases in Trf1 mRNA expression, C2C12 myotubes were treated with the calcium ionophore, A23187. In response to the A23187, Trf1 gene expression was significantly reduced, coupled with significant increases in p38 phosphorylation, similar to in vivo data. C2C12 myotubes pretreated with a p38 inhibitor (SB-202190) prevented the A23187-induced decrease in Trf1 mRNA expression, indicating a link between Trf1 gene expression and p38 MAPK activation. While it is too early to definitively report the effect of exercise on telomere biology in rodents or humans, these data provide important mechanistic insights into the paradoxical telomere shortening that occurs in skeletal muscle in response to chronic exercise in mice.