Redox signaling regulates skeletal muscle remodeling in response to exercise and prolonged inactivity.

Skeletal muscle fibers are malleable and undergo rapid remodeling in response to increased contractile activity (i.e., exercise) or prolonged periods of muscle inactivity (e.g., prolonged bedrest). Exploration of the cell signaling pathways regulating these skeletal muscle adaptations reveal that redox signaling pathways play a key role in the control of muscle remodeling during both exercise and prolonged muscle inactivity. In this regard, muscular exercise results in an acute increase in the production of reactive oxygen species (ROS) in the contracting fibers; however, this contraction-induced rise in ROS production rapidly declines when contractions cease. In contrast, prolonged muscle disuse results in a chronic elevation in ROS production within the inactive fibers. This difference in the temporal pattern of ROS production in muscle during exercise and muscle inactivity stimulates divergent cell-signaling pathways that activate both genomic and nongenomic mechanisms to promote muscle remodeling. This review examines the role that redox signaling plays in skeletal muscle adaptation in response to both prolonged muscle inactivity and endurance exercise training. We begin with a summary of the sites of ROS production in muscle fibers followed by a review of the cellular antioxidants that are responsible for regulation of ROS levels in the cell. We then discuss the specific redox-sensitive signaling pathways that promote skeletal muscle adaptation in response to both prolonged muscle inactivity and exercise. To stimulate future research, we close with a discussion of unanswered questions in this exciting field.

Exercise Training and Skeletal Muscle Antioxidant Enzymes: An Update.

The pivotal observation that muscular exercise is associated with oxidative stress in humans was first reported over 45 years ago. Soon after this landmark finding, it was discovered that contracting skeletal muscles produce oxygen radicals and other reactive species capable of oxidizing cellular biomolecules. Importantly, the failure to eliminate these oxidant molecules during exercise results in oxidation of cellular proteins and lipids. Fortuitously, muscle fibers and other cells contain endogenous antioxidant enzymes capable of eliminating oxidants. Moreover, it is now established that several modes of exercise training (e.g., resistance exercise and endurance exercise) increase the expression of numerous antioxidant enzymes that protect myocytes against exercise-induced oxidative damage. This review concisely summarizes the impact of endurance, high-intensity interval, and resistance exercise training on the activities of enzymatic antioxidants within skeletal muscles in humans and other mammals. We also discuss the evidence that exercise-induced up-regulation of cellular antioxidants reduces contraction-induced oxidative damage in skeletal muscles and has the potential to delay muscle fatigue and improve exercise performance. Finally, in hopes of stimulating further research, we also discuss gaps in our knowledge of exercise-induced changes in muscle antioxidant capacity.

Age-associated effects of a concurrent cognitive task on gait speed and stability during narrow-base walking.

BACKGROUND: In older adults, changes in speed and stability during walking are associated with impaired balance and increased fall risk. Narrow-base walking requires increased frontal plane stability and can be used to assess postural control while walking. Performance of a concurrent cognitive task (dual task) may further increase the complexity of walking, potentially allowing identification of individuals with instability that is not detected under single-task conditions. The purpose of this study was to examine age-associated effects of a cognitive task on speed and frontal plane stability during narrow-base walking. METHODS: Thirty-four healthy adults participated, categorized by age: <65, 65-74, and > or =75 years. Participants walked at a comfortable pace within a narrow path under both single- and dual-task conditions. We examined spatiotemporal variables and frontal plane center of mass (CoM) parameters using a 13-segment biomechanical model. RESULTS: Increasing age (p <.001) and the performance of a concurrent cognitive task (p <.001) were both associated with decreased speed, with no interaction between these factors. Frontal plane CoM displacement and velocity increased with increasing age (both p <.001), but dual-task performance had no effect on these variables (both p >.450). CONCLUSIONS: Age-associated changes in both speed and stability are observed during narrow-base walking. Among this sample of healthy older adults, the addition of a concurrent cognitive task resulted in reduced speed, with no effect on frontal plane stability. Further research is needed to determine if dual-task, narrow-base walking is a sensitive and specific approach to identifying older adults at risk for falls.

The effects of age on medio-lateral stability during normal and narrow base walking.

We examined age-related differences in frontal plane stability during performance of narrow base (NB) walking relative to usual gait. A cross-sectional analysis of participants from the Baltimore Longitudinal Study of Aging (BLSA) was performed on data from the BLSA Motion Analysis Laboratory. Participants were 34 adults aged 54-92 without history of falls. We measured step error rates during NB gait and spatial-temporal parameters, frontal plane stability, and gait variability during usual and NB gait. There was a non-significant age-associated linear increase in step error rate (P=0.12) during NB gait. With increasing age, step width increased (P=0.002) and step length and stride velocity decreased (P<0.001), especially during NB gait. Age-associated increases in medio-lateral (M-L) center of mass (COM) peak velocity (P<0.001) and displacement (P=0.005) were also greater during NB compared to usual gait. With increasing age there was greater variability in stride velocity (P=0.001) and step length (P<0.001) under both conditions. Age-associated differences related to M-L COM stability suggest that the quantification of COM control during NB gait may improve identification of older persons at increased falls risk.

Hypercortisolemic depression is associated with the metabolic syndrome in late-life.

INTRODUCTION: Depression has been hypothesized to be associated with metabolic abnormalities which increase the risk of cardiovascular disease (CVD) and diabetes. Such a link could be due to increased HPA-axis activity. This study investigates the cross-sectional relationship between depression, urinary cortisol and metabolic syndrome in an older population. METHODS: Data are from 867 participants of the InChianti Study, aged 65 years. Depressive symptoms were assessed using the CES-D scale; cortisol levels were determined in 24-h urine samples. Metabolic syndrome was defined as three or more of the following: abdominal obesity, high triglycerides, low HDL cholesterol, high blood pressure, and high fasting glucose. RESULTS: Clinically relevant depressed mood (CES-D20) was present in 20.6% of the sample, and 24.5% had the metabolic syndrome. After adjustment for sociodemographics and health indicators, depression score (per SD increase: OR=1.20, 95% CI=1.02-1.41) and urinary cortisol level (per SD increase: OR=1.23, 95% CI=1.01-1.51) were significantly associated with presence of metabolic syndrome. There was, however, a significant interaction (p=0.003) between depressed mood and urinary cortisol in the probability of having metabolic syndrome. The odds of metabolic syndrome in persons with both depressed mood and urinary cortisol excretion in the highest tertile was 1.84 (95% CI=1.02-3.34) compared to persons with neither condition. DISCUSSION: This study suggests a synergistic relationship between depression, cortisol and metabolic syndrome. Hypercortisolemic depression may constitute a specific risk group for the metabolic syndrome.

Sarcopenic obesity and inflammation in the InCHIANTI study.

The aging process is often paralleled by decreases in muscle and increases in fat mass. At the extreme these two processes lead to a condition known as "sarcopenic obesity" (Roubenoff R. Ann NY Acad Sci 904: 553-557, 2000). Research suggests that inflammatory cytokines produced by adipose tissue, especially visceral fat, accelerate muscle catabolism and thus contribute to the vicious cycle that initiates and sustains sarcopenic obesity. We tested the hypothesis that obesity and poor muscle strength, hallmarks of sarcopenic obesity, are associated with high circulating levels of proinflammatory cytokines in a random sample of the residents of two municipalities in the Chianti geographic area (Tuscany, Italy). The study sample consisted of 378 men and 493 women 65 yr and older with complete data on anthropometrics, handgrip strength, and inflammatory markers. Participants were cross-classified according to sex-specific tertiles of waist circumference and grip strength and according to a cut point for obesity of body mass index > or =30 kg/m(2). After adjusting for age, sex, education, smoking history, physical activity, and history of comorbid diseases, components of sarcopenic obesity were associated with elevated levels of IL-6, C-reactive protein, IL-1 receptor antagonist, and soluble IL-6 receptor (P < 0.05). Our findings suggest that global obesity and, to a greater extent, central obesity directly affect inflammation, which in turn negatively affects muscle strength, contributing to the development and progression of sarcopenic obesity. These results suggest that proinflammatory cytokines may be critical in both the development and progression of sarcopenic obesity.

Effects of blueberry supplementation on measures of functional mobility in older adults.

Limited functional mobility in older adults has been associated with declines in tests of motor, psychomotor, and executive function. Animal studies have demonstrated reversals in indices of motor and psychomotor function via supplementation with polyphenolic-rich foods such as blueberries. The purpose of this study was to examine whether 6 weeks of daily consumption of 2 cups of frozen blueberries affects functional mobility in older adults. Pre- and post-intervention assessments of grip strength, simple reaction time, adaptive gait, and executive function were completed for older adults (age >60 years) partially randomly assigned to a blueberry (BB) supplementation or a carrot juice drink control (CAR) group. Paired t tests were used to assess within-group effects for outcome variables in each supplementation group, and a mixed-model analysis of covariance (ANCOVA) was used to determine group (CAR vs. BB) differences. Mixed-model analysis indicated that the BB group demonstrated significant improvements relative to the CAR group in performance (i.e., number of step errors) of a challenging dual-task adaptive gait test that were independent of differences in gait speed. Within only the BB group, significant improvements were also seen in 3 other measures (i.e., usual gait speed; number of step errors during single-task adaptive gait; and gait speed during dual-task adaptive gait). These preliminary findings support the hypothesis that blueberry supplementation may provide an effective countermeasure to age-related declines in functional mobility and serve as justification for an expansion to larger trials to more fully assess this nonpharmacologic approach to maintaining optimal mobility and independence.

Skeletal muscle strength as a predictor of all-cause mortality in healthy men.

Low muscle strength is associated with mortality, presumably as a result of low muscle mass (sarcopenia) and physical inactivity. Grip strength was longitudinally collected in 1071 men over a 25-year period. Muscle mass was estimated by using 24-hour creatinine excretion and physical activity values, obtained by questionnaire. Survival analysis examined the impact of grip strength and rate of change in strength on all-cause mortality over 40 years. Lower and declining strength are associated with increased mortality, independent of physical activity and muscle mass. In men <60 years, rate of loss of strength was more important than the actual levels. In men >/=60 years, strength was more protective than the rate of loss, which persisted when muscle mass was considered. Strength and rate of change in strength contribute to the impact of sarcopenia on mortality. Although muscle mass and physical activity are important, they do not completely account for the impact of strength and changes in strength.

Interleukin-6 (IL6) genotype is associated with fat-free mass in men but not women.

We studied the association of the G-174C promoter polymorphism in the interleukin-6 gene (IL6) with total body fat and fat-free mass (FFM) in 242 men and women (IL6 genotypes: G/G, n = 87; G/C, n = 100; C/C, n = 55) across the adult age span (21-92 years). In men, but not women (significant genotype by sex interactions; p =.023-.048), the C/C group exhibited significantly lower total FFM than the G/G group (54.7 +/- 0.8 kg vs 57.2 +/- 0.7 kg, respectively, p =.020), as well as significantly lower FFM of the lower limbs compared with the G/G group (18.4 +/- 0.3 kg vs 19.8 +/- 0.3 kg, respectively, p =.004). No significant genotype differences were observed in total body fat mass in either men or women. The results indicate that the IL6 G-174C polymorphism is significantly associated with FFM in men but not women.

Arm-cranking muscle power and arm isometric muscle strength are independent predictors of all-cause mortality in men.

Poor muscle strength is associated with mortality, presumably due to low muscle mass. Notably, muscle power declines more rapidly than muscle strength with increasing age, which may be related to more complex central nervous system movement control. We examined arm-cranking power against four workloads and isometric strength measured in the upper extremities of 993 men longitudinally tested over a 25-yr period. Muscle mass was estimated by using 24-h creatinine excretion; physical activity was assessed by self-reported questionnaire. Muscle power and strength were modeled by time by using mixed-effects models, which developed regression equations for each individual. The first derivative of these equations estimated rate of change in strength or power at each evaluation. Survival analyses, using the counting method, examined the impact of strength, power, and their rates of change on all-cause mortality while adjusting for age. Arm-cranking power [relative risk (rr) = 0.984 per 100 kg.m.min(-1), P < 0.001] was a stronger predictor of mortality than was arm strength (rr = 0.986 per 10 kg, P = not significant), whereas rate of power change (rr = 0.989 per 100 kg.min(-1).yr(-1)) and rate of arm strength change (rr = 0.888 per 10 kg/yr) were risks independent of the power or strength levels. The impacts of power and strength were partially independent of muscle mass and physical activity. The risk of mortality was similar across the four power workloads (rr = 0.93-0.96 per 100 kg.m.min(-1)), whereas the lowest load generated less than one-half the power as the higher loads. Arm-cranking power is a risk factor for mortality, independent of muscle strength, physical activity, and muscle mass. The impact is found with loads that do not generate maximal power, suggesting an important role for motor coordination and speed of movement.

Insulin-like growth factor-2 genotype, fat-free mass, and muscle performance across the adult life span.

The influence of insulin-like growth factor-2 (IGF2) genotype on total body fat-free mass (FFM), muscle strength, and sustained power (SP) was evaluated repeatedly at approximately 2-yr intervals in two cohorts from the Baltimore Longitudinal Study of Aging. Cohort 1 was comprised of 94 men tested for isometric grip strength and SP. Cohort 2 was comprised of 246 men and 239 women tested for total body FFM and isokinetic peak torque. Subjects were retrospectively genotyped for the IGF2 gene's ApaI polymorphism. Differences between genotype groups for total FFM, strength, and SP at first visit, at peak age (35 yr), at age 65, and across the adult age span were analyzed using either two-sample t-tests or mixed-effects models, depending on the specific comparisons made. Isokinetic arm strength at the time of first visit was lower in A/A men than in G/G men (P < 0.05). Compared with G/G women, A/A women had lower total body FFM, lower isokinetic arm and leg strength at the time of first visit, and lower values at age 35 (all P < 0.05) for these muscle phenotypes. Furthermore, this difference between the genotype groups was maintained at age 65 and across the adult age span (P < 0.05). No genotype-associated differences in rates of loss of grip strength or SP were found in cohort 1. These results from cohort 2 support the hypothesis that variation within a gene known to influence developing muscle affects muscle mass and muscle function in later life.

Association between energy availability and physical activity in older adults.

OBJECTIVE: Age-related declines in physical activity are commonly observed in human and animal populations, but their physiologic bases are not fully understood. The authors hypothesize that a lack of available energy contributes to low levels of activity in older persons. DESIGN: Cross-sectional analyses of relationships between physical activity level and energy availability were performed in 602 community-dwelling volunteers aged 45-91 yrs from the Baltimore Longitudinal Study of Aging. Energy expenditure was measured at rest and during a maximal 400-m walk for calculation of "available energy." Overall and vigorous physical activity levels were assessed using standardized questionnaires. General linear regression models were used to assess the relationships between available energy and general and vigorous physical activity, and stratified analyses were used to analyze the possible differential association between available energy and physical activity across high and low (peak sustained walking oxygen consumption per unit time, <18.3 ml of oxygen per kilogram per minute) levels of aerobic fitness. RESULTS: Low available energy was associated with low levels of total physical activity (ß = 64.678, P = 0.015) and vigorous activity (ß = 9.123, P < 0.0001). The direct relationship between available energy and physical activity was particularly strong in persons categorized as having low aerobic fitness between available energy and physical activity with both total (ß = 119.783, P = 0.022) and vigorous activity (ß = 10.246, P = 0.015) and was independent of body composition and age. CONCLUSIONS: The findings from this study support the hypothesis that available energy promotes the maintenance of physical activity in older persons. The findings also run counter to the perception that age-related declines in physical activity are primarily societally or behaviorally driven.

Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men.

Muscle mass and strength losses during aging may be associated with declining levels of serum testosterone (T) in men. Few studies have shown a direct relationship between T and muscle mass and strength. Subjects were 262 men, aged 24-90 yr, from the Baltimore Longitudinal Study of Aging, who had T and sex hormone-binding globulin sex hormone-binding globulin (SHBG) measurements, from which the free T index (FTI) was calculated (T/SHBG) from serum samples collected longitudinally since 1963, total body fat mass and arm and leg fat-free mass (FFM) by dual-energy X-ray absorptiometry and arm and leg strength by dynanomometry. Mixed-effects models estimated T and FTI at the time of mass and strength measurements. Age, total body fat, arm and leg FFM, T, and FTI were significantly associated with concentric and eccentric strength. FTI, not T, was modestly, but directly, related to arm and leg strength after fat, arm and leg FFM, height, and age were accounted for and indirectly through body mass. FTI is a better predictor of arm and leg strength than T in aging men.