Damien M. Callahan

Age-related fatigue resistance in the knee extensor muscles is specific to contraction mode

The question of whether skeletal muscle fatigue is preserved or enhanced in older adults is a point of controversy. Disparate findings may be attributed to differences in subject population and study protocols, including contraction mode. The purpose of this study was to test the hypotheses that healthy older (65–80 years of age, 8 males and 8 females) adults who were matched to young adults (21–35 years of age; 8 males and 8 females) with similar physical activity levels would: (1) fatigue less during isometric knee extensor (KE) contractions, but (2) would show similar fatigue during dynamic KE contractions performed at 120° s−1. Fatigue was induced with 4 minutes of intermittent, isometric, or dynamic maximal voluntary contractions, performed on separate days. Electrically stimulated contractions were used to evaluate central activation during both fatigue protocols. Older subjects maintained a higher percentage of baseline maximum voluntary contraction (MVC) torque than young subjects during isometric contractions (mean ± SE: 71 ± 3% and 57 ± 3%, respectively, P < 0.01). In contrast, there was no difference between age groups in torque maintenance during dynamic contractions (43 ± 3% and 44 ± 3%, respectively, P = 0.86). For both groups, changes in electrically stimulated and voluntary contractions followed similar trends, suggesting that central activation did not play a role in the age‐related differences in fatigue. Fatigue during the isometric protocol was associated with fatigue during the dynamic protocol in the young group only (r = 0.62, P = 0.01), suggesting that distinct mechanisms influence fatigue during isometric and dynamic contractions in older adults. Muscle Nerve 39: 692–702, 2009

Age-related changes in oxidative capacity differ between locomotory muscles and are associated with physical activity behavior.

There is discrepancy in the literature regarding the degree to which old age affects muscle bioenergetics. These discrepancies are likely influenced by several factors, including variations in physical activity (PA) and differences in the muscle group investigated. To test the hypothesis that age may affect muscles differently, we quantified oxidative capacity of tibialis anterior (TA) and vastus lateralis (VL) muscles in healthy, relatively sedentary younger (8 YW, 8 YM; 21-35 years) and older (8 OW, 8 OM; 65-80 years) adults. To investigate the effect of physical activity on muscle oxidative capacity in older adults, we compared older sedentary women to older women with mild-to-moderate mobility impairment and lower physical activity (OIW, n = 7), and older sedentary men with older active male runners (OAM, n = 6). Oxidative capacity was measured in vivo as the rate constant, k(PCr), of postcontraction phosphocreatine recovery, obtained by (31)P magnetic resonance spectroscopy following maximal isometric contractions. While k(PCr) was higher in TA of older than activity-matched younger adults (28%; p = 0.03), older adults had lower k(PCr) in VL (23%; p = 0.04). In OIW compared with OW, k(PCr) was lower in VL (∼45%; p = 0.01), but not different in TA. In contrast, OAM had higher k(PCr) than OM (p = 0.03) in both TA (41%) and VL (54%). In older adults, moderate-to-vigorous PA was positively associated with k(PCr) in VL (r = 0.65, p < 0.001) and TA (r = 0.41, p = 0.03). Collectively, these results indicate that age-related changes in oxidative capacity vary markedly between locomotory muscles, and that altered PA behavior may play a role in these changes.

Effect of old age on human skeletal muscle force-velocity and fatigue properties.

It is generally accepted that the muscles of aged individuals contract with less force, have slower relaxation rates, and demonstrate a downward shift in their force-velocity relationship. The factors mediating age-related differences in skeletal muscle fatigue are less clear. The present study was designed to test the hypothesis that age-related shifts in the force-velocity relationship impact the fatigue response in a velocity-dependent manner. Three fatigue protocols, consisting of intermittent, maximum voluntary knee extension contractions performed for 4 min, were performed by 11 young (23.5 ± 0.9 yr, mean ± SE) and 10 older (68.9 ± 4.3) women. The older group fatigued less during isometric contractions than the young group (to 71.1 ± 3.7% initial torque and 59.8 ± 2.5%, respectively; P = 0.02), while the opposite was true during contractions performed at a relatively high angular velocity of 270°·s(-1) (old: 28.0 ± 3.9% initial power, young: 52.1 ± 6.9%; P < 0.01). Fatigue was not different (P = 0.74) between groups during contractions at an intermediate velocity, which was selected for each participant based on their force-velocity relationship. There was a significant association between force-velocity properties and fatigue induced by the intermediate-velocity fatigue protocol in the older (r = 0.72; P = 0.02) and young (r = 0.63; P = 0.04) groups. These results indicate that contractile velocity has a profound impact on age-related skeletal muscle fatigue resistance and suggest that changes in the force-velocity relationship partially mediate this effect.

Age-related slowing of myosin actin cross-bridge kinetics is sex specific and predicts decrements in whole skeletal muscle performance in humans

We hypothesize that age-related skeletal muscle dysfunction and physical disability may be partially explained by alterations in the function of the myosin molecule. To test this hypothesis, skeletal muscle function at the whole muscle, single fiber, and molecular levels was measured in young (21-35 yr) and older (65-75 yr) male and female volunteers with similar physical activity levels. After adjusting for muscle size, older adults had similar knee extensor isometric torque values compared with young, but had lower isokinetic power, most notably in women. At the single-fiber and molecular levels, aging was associated with increased isometric tension, slowed myosin actin cross-bridge kinetics (longer myosin attachment times and reduced rates of myosin force production), greater myofilament lattice stiffness, and reduced phosphorylation of the fast myosin regulatory light chain; however, the age effect was driven primarily by women (i.e., age-by-sex interaction effects). In myosin heavy chain IIA fibers, single-fiber isometric tension and molecular level mechanical and kinetic indexes were correlated with whole muscle isokinetic power output. Collectively, considering that contractile dysfunction scales up through various anatomical levels, our results suggest a potential sex-specific molecular mechanism, reduced cross-bridge kinetics, contributes to the reduced physical capacity with aging in women. Thus these results support our hypothesis that age-related alterations in the myosin molecule contribute to skeletal muscle dysfunction and physical disability and indicate that this effect is stronger in women.

Skeletal muscle myofilament adaptations to aging, disease, and disuse and their effects on whole muscle performance in older adult humans.

Skeletal muscle contractile function declines with aging, disease, and disuse. In vivo muscle contractile function depends on a variety of factors, but force, contractile velocity and power generating capacity ultimately derive from the summed contribution of single muscle fibers. The contractile performance of these fibers are, in turn, dependent upon the isoform and function of myofilament proteins they express, with myosin protein expression and its mechanical and kinetic characteristics playing a predominant role. Alterations in myofilament protein biology, therefore, may contribute to the development of functional limitations and disability in these conditions. Recent studies suggest that these conditions are associated with altered single fiber performance due to decreased expression of myofilament proteins and/or changes in myosin-actin cross-bridge interactions. Furthermore, cellular and myofilament-level adaptations are related to diminished whole muscle and whole body performance. Notably, the effect of these various conditions on myofilament and single fiber function tends to be larger in older women compared to older men, which may partially contribute to their higher rates of disability. To maintain functionality and provide the most appropriate and effective countermeasures to aging, disease, and disuse in both sexes, a more thorough understanding is needed of the contribution of myofilament adaptations to functional disability in older men and women and their contribution to tissue level function and mobility impairment.

In vivo oxidative capacity varies with muscle and training status in young adults

It is well established that exercise training results in increased muscle oxidative capacity. Less is known about how oxidative capacities in distinct muscles, in the same individual, are affected by different levels of physical activity. We hypothesized that 1) trained individuals would have higher oxidative capacity than untrained individuals in both tibialis anterior (TA) and vastus lateralis (VL) and 2) oxidative capacity would be higher in TA than VL in untrained, but not in trained, individuals. Phosphorus magnetic resonance spectroscopy was used to measure the rate of phosphocreatine recovery (k(PCr)), which reflects the rate of oxidative phosphorylation, following a maximal voluntary isometric contraction of the TA and VL in healthy untrained (7 women, 7 men, 25.7 +/- 3.6 yr; mean +/- SD) and trained (5 women, 7 men, 27.5 +/- 3.4 yr) adults. Daily physical activity levels were measured using accelerometry. The trained group spent threefold more time ( approximately 90 vs. approximately 30 min/day; P < 0.001) in moderate to vigorous physical activity (MVPA). Overall, k(PCr) was higher in VL than in TA (P = 0.01) and higher in trained than in untrained participants (P < 0.001). The relationship between k(PCr) and MVPA was more robust in VL (r = 0.64, P = 0.001, n = 25) than in TA (r = 0.38, P = 0.06, n = 25). These results indicate greater oxidative capacity in vivo in trained compared with untrained individuals in two distinct muscles of the lower limb and provide novel evidence of higher oxidative capacity in VL compared with TA in young humans, irrespective of training status. The basis for this difference is not known at this time but likely reflects a difference in usage patterns between the muscles.

Age-related structural alterations in human skeletal muscle fibers and mitochondria are sex specific: relationship to single-fiber function

Age-related loss of skeletal muscle mass and function is implicated in the development of disease and physical disability. However, little is known about how age affects skeletal muscle structure at the cellular and ultrastructural levels or how such alterations impact function. Thus we examined skeletal muscle structure at the tissue, cellular, and myofibrillar levels in young (21-35 yr) and older (65-75 yr) male and female volunteers, matched for habitual physical activity level. Older adults had smaller whole muscle tissue cross-sectional areas (CSAs) and mass. At the cellular level, older adults had reduced CSAs in myosin heavy chain II (MHC II) fibers, with no differences in MHC I fibers. In MHC II fibers, older men tended to have fewer fibers with large CSAs, while older women showed reduced fiber size across the CSA range. Older adults showed a decrease in intermyofibrillar mitochondrial size; however, the age effect was driven primarily by women (i.e., age by sex interaction effect). Mitochondrial size was inversely and directly related to isometric tension and myosin-actin cross-bridge kinetics, respectively. Notably, there were no intermyofibrillar or subsarcolemmal mitochondrial fractional content or myofilament ultrastructural differences in the activity-matched young and older adults. Collectively, our results indicate age-related reductions in whole muscle size do not vary by sex. However, age-related structural alterations at the cellular and subcellular levels are different between the sexes and may contribute to different functional phenotypes in ways that modulate sex-specific reductions in physical capacity with age.

Molecular mechanisms underlying skeletal muscle weakness in human cancer: reduced myosin-actin cross-bridge formation and kinetics

Many patients with cancer experience physical disability following diagnosis, although little is known about the mechanisms underlying these functional deficits. To characterize skeletal muscle adaptations to cancer in humans, we evaluated skeletal muscle structure and contractile function at the molecular, cellular, whole-muscle, and whole-body level in 11 patients with cancer (5 cachectic, 6 noncachectic) and 6 controls without disease. Patients with cancer showed a 25% reduction in knee extensor isometric torque after adjustment for muscle mass (P < 0.05), which was strongly related to diminished power output during a walking endurance test (r = 0.889; P < 0.01). At the cellular level, single fiber isometric tension was reduced in myosin heavy chain (MHC) IIA fibers (P = 0.05) in patients with cancer, which was explained by a reduction (P < 0.05) in the number of strongly bound cross-bridges. In MHC I fibers, myosin-actin cross-bridge kinetics were reduced in patients, as evidenced by an increase in myosin attachment time (P < 0.01); and reductions in another kinetic parameter, myosin rate of force production, predicted reduced knee extensor isometric torque (r = 0.689; P < 0.05). Patients with cancer also exhibited reduced mitochondrial density (-50%; P < 0.001), which was related to increased myosin attachment time in MHC I fibers (r = -0.754; P < 0.01). Finally, no group differences in myofilament protein content or ultrastructure were noted that explained the observed functional alterations. Collectively, our results suggest reductions in myofilament protein function as a potential molecular mechanism contributing to muscle weakness and physical disability in human cancer.

Muscle disuse alters skeletal muscle contractile function at the molecular and cellular levels in older adult humans in a sex-specific manner

Muscle disuse that accompanies ageing and chronic disease may hasten physical disability by impairing skeletal muscle contractility. We compared skeletal muscle contractile function at the various anatomic levels between two groups of older men and women matched for sex, health status and body size, of which one group was habitually active and the other inactive. Muscle disuse reduced force generation, power output and contractile velocity in single muscle fibres, with differential adaptations in some parameters in men and women. Sex‐specific cellular phenotypes were explained by differential adaptations in molecular muscle function. Moreover, aspects of the molecular functional phenotype apparent in inactive women could be recapitulated in vitro by chemical modification of protein thiols. Our results identify molecular and cellular contractile dysfunction in skeletal muscle that may contribute to reduced physical function with muscle disuse, with sex‐specific differences that may explain a greater disposition towards disability in women.

SKELETAL MUSCLE PROTEIN METABOLISM IN HUMAN HEART FAILURE

Purpose of reviewThis review considers evidence that the clinical condition of heart failure alters skeletal muscle protein synthesis and/or breakdown to promote skeletal muscle wasting and functional decrements that ultimately contribute to the symptomology of the disease. Recent findingsAdvanced HF is frequently accompanied by muscle atrophy and a cachectic phenotype. Protein metabolic derangements that promote this phenotype are understudied and poorly understood. Instead, most investigations have evaluated regulatory hormones/signaling pathways thought to be reflective of protein synthesis and breakdown. Several of these recent studies have provided exciting data suggesting that the dysfunctional myocardium releases catabolic agents that could promote the skeletal muscle myopathic phenotype either directly or through modulation of other regulatory systems (e.g., energy balance). SummaryAlthough our understanding of skeletal muscle atrophy and dysfunction in heart failure is limited, recent studies have provided clues about the nature and timing of protein metabolic dysfunction. More specifically, skeletal muscle protein metabolic derangements likely evolve during periods of disease-related stress (i.e., acute disease exacerbation and hospitalization) and potentially derive in part, from signals promoted in the damaged/dysfunctional myocardium. Despite these compelling studies, there is a surprising lack of data regarding the nature or timing of specific protein metabolic defects in heart failure.