Predicting myosin heavy chain isoform from postdissection fiber length in human skeletal muscle fibers.

Experimental techniques in single human skeletal muscle cells require manual dissection. Unlike other mammalian species, human skeletal muscle is characterized by a heterogeneous mixture of myosin heavy chain (MHC) isoforms, typically used to define "fiber type," which profoundly influences cellular function. Therefore, it is beneficial to predict MHC isoform at the time of dissection, facilitating a more balanced fiber-type distribution from a potentially imbalanced sample. Although researchers performing single fiber dissection report predicting fiber-type based on mechanical properties of fibers upon dissection, a rigorous examination of this approach has not been performed. Therefore, we measured normalized fiber length (expressed as a % of the length of the bundle from which the fiber was dissected) in single fibers immediately following dissection. Six hundred sixty-eight individual fibers were dissected from muscle tissue samples from healthy, young adults to assess whether this characteristic could differentiate fibers containing MHC I ("slow" fiber type) or not ("fast" fiber type). Using receiver operator characteristic (ROC) curves, we found that differences in normalized fiber length (114 ± 13%, MHC I; 124 ± 17%, MHC IIA, P < 0.01) could be used to predict fiber type with excellent reliability (area under the curve = 0.72). We extended these analyses to include older adults (2 females, 1 male) to demonstrate the durability of this approach in fibers with likely different morphology and mechanical characteristics. We report that MHC isoform expression in human skeletal muscle fibers can be predicted at the time of dissection, regardless of origin.NEW & NOTEWORTHY A priori estimation of myosin heavy chain (MHC) isoform in individual muscle fibers may bias the relative abundance of fiber types in subsequent assessment. Until now, no standardized assessment approach has been proposed to characterize fibers at the time of dissection. We demonstrate an approach based on normalized fiber length that may dramatically bias a sample toward slow twitch (MHC I) or fast twitch (not MHC I) fiber populations.

Fatiguing exercise reduces cellular passive Young's modulus in human vastus lateralis muscle.

Previous studies demonstrated that acute fatiguing exercise transiently reduces whole-muscle stiffness, which might contribute to increased risk of injury and impaired contractile performance. We sought to elucidate potential intracellular mechanisms underlying these reductions. To that end, the cellular passive Young's modulus was measured in muscle fibres from healthy, young males and females. Eight volunteers (four male and four female) completed unilateral, repeated maximal voluntary knee extensions until task failure, immediately followed by bilateral percutaneous needle muscle biopsy of the post-fatigued followed by the non-fatigued control vastus lateralis. Muscle samples were processed for mechanical assessment and separately for imaging and phosphoproteomics. Fibres were passively (pCa 8.0) stretched incrementally to 156% of initial sarcomere length to assess Young's modulus, calculated as the slope of the resulting stress-strain curve at short (sarcomere length = 2.4-3.0 µm) and long (sarcomere length = 3.2-3.8 µm) lengths. Titin phosphorylation was assessed by liquid chromatography followed by high-resolution mass spectrometry. The passive modulus was significantly reduced in post-fatigued versus control fibres from male, but not female, participants. Post-fatigued samples showed altered phosphorylation of five serine residues (four located within the elastic region of titin) but did not exhibit altered active tension or sarcomere ultrastructure. Collectively, these results suggest that acute fatigue is sufficient to alter phosphorylation of skeletal titin in multiple locations. We also found reductions in the passive modulus, consistent with prior reports in the literature investigating striated muscle stiffness. These results provide mechanistic insight contributing to the understanding of dynamic regulation of whole-muscle tissue mechanics in vivo. HIGHLIGHTS: What is the central question of this study? Previous studies have shown that skeletal muscle stiffness is reduced following a single bout of fatiguing exercise in whole muscle, but it is not known whether these changes manifest at the cellular level, and their potential mechanisms remain unexplored. What is the main finding and its importance? Fatiguing exercise reduces cellular stiffness in skeletal muscle from males but not females, suggesting that fatigue alters tissue compliance in a sex-dependent manner. The phosphorylation status of titin, a potential mediator of skeletal muscle cellular stiffness, is modified by fatiguing exercise. Previous studies have shown that passive skeletal muscle stiffness is reduced following a single bout of fatiguing exercise. Lower muscle passive stiffness following fatiguing exercise might increase risk for soft-tissue injury; however, the underlying mechanisms of this change are unclear. Our findings show that fatiguing exercise reduces the passive Young's modulus in skeletal muscle cells from males but not females, suggesting that intracellular proteins contribute to reduced muscle stiffness following repeated loading to task failure in a sex-dependent manner. The phosphorylation status of the intracellular protein titin is modified by fatiguing exercise in a way that might contribute to altered muscle stiffness after fatiguing exercise. These results provide important mechanistic insight that might help to explain why biological sex impacts the risk for soft-tissue injury with repeated or high-intensity mechanical loading in athletes and the risk of falls in older adults.

Skeletal Muscle Compliance and Echogenicity in Resistance-Trained and Nontrained Women.

ABSTRACT: Mongold, SJ, Ricci, AW, Hahn, ME, and Callahan, DM. Skeletal muscle compliance and echogenicity in resistance-trained and nontrained women. J Strength Cond Res 38(4): 671-680, 2024-Noninvasive assessment of muscle mechanical properties in clinical and performance settings tends to rely on manual palpation and emphasizes examination of musculotendinous stiffness. However, measurement standards are highly subjective. The purpose of the study was to compare musculotendinous stiffness in adult women with varying resistance training history while exploring the use of multiple tissue compliance measures. We identified relationships between tissue stiffness and morphology, and tested the hypothesis that combining objective measures of morphology and stiffness would better predict indices of contractile performance. Resistance-trained (RT) women (n = 11) and nontrained (NT) women (n = 10) participated in the study. Muscle echogenicity and morphology were measured using B-mode ultrasonography (US). Vastus lateralis (VL) and patellar tendon (PT) stiffness were measured using digital palpation and US across submaximal isometric contractions. Muscle function was evaluated during maximal voluntary isometric contraction (MVIC) of the knee extensors (KEs). Resistance trained had significantly greater PT stiffness and reduced echogenicity (p < 0.01). Resistance trained also had greater strength per body mass (p < 0.05). Muscle echogenicity was strongly associated with strength and rate of torque development (RTD). Patellar tendon passive stiffness was associated with RTD normalized to MVIC (RTDrel; r = 0.44, p < 0.05). Patellar tendon stiffness was greater in RT young women. No predictive models of muscle function incorporated both stiffness and echogenicity. Because RTDrel is a clinically relevant measure of rehabilitation in athletes and can be predicted by digital palpation, this might represent a practical and objective measure in settings where RTD may not be easy to measure directly.

Skeletal muscle atrophy and dysfunction in breast cancer patients: role for chemotherapy-derived oxidant stress.

How breast cancer and its treatments affect skeletal muscle is not well defined. To address this question, we assessed skeletal muscle structure and protein expression in 13 women who were diagnosed with breast cancer and receiving adjuvant chemotherapy following tumor resection and 12 nondiseased controls. Breast cancer patients showed reduced single-muscle fiber cross-sectional area and fractional content of subsarcolemmal and intermyofibrillar mitochondria. Drugs commonly used in breast cancer patients (doxorubicin and paclitaxel) caused reductions in myosin expression, mitochondrial loss, and increased reactive oxygen species (ROS) production in C2C12 murine myotube cell cultures, supporting a role for chemotherapeutics in the atrophic and mitochondrial phenotypes. Additionally, concurrent treatment of myotubes with the mitochondrial-targeted antioxidant MitoQ prevented chemotherapy-induced myosin depletion, mitochondrial loss, and ROS production. In patients, reduced mitochondrial content and size and increased expression and oxidation of peroxiredoxin 3, a mitochondrial peroxidase, were associated with reduced muscle fiber cross-sectional area. Our results suggest that chemotherapeutics may adversely affect skeletal muscle in patients and that these effects may be driven through effects of these drugs on mitochondrial content and/or ROS production.

Mechanisms of in vivo muscle fatigue in humans: investigating age-related fatigue resistance with a computational model.

KEY POINTS: Muscle fatigue can be defined as the transient decrease in maximal force that occurs in response to muscle use. Fatigue develops because of a complex set of changes within the neuromuscular system that are difficult to evaluate simultaneously in humans. The skeletal muscle of older adults fatigues less than that of young adults during static contractions. The potential sources of this difference are multiple and intertwined. To evaluate the individual mechanisms of fatigue, we developed an integrative computational model based on neural, biochemical, morphological and physiological properties of human skeletal muscle. Our results indicate first that the model provides accurate predictions of fatigue and second that the age-related resistance to fatigue is due largely to a lower reliance on glycolytic metabolism during contraction. This model should prove useful for generating hypotheses for future experimental studies into the mechanisms of muscle fatigue. ABSTRACT: During repeated or sustained muscle activation, force-generating capacity becomes limited in a process referred to as fatigue. Multiple factors, including motor unit activation patterns, muscle fibre contractile properties and bioenergetic function, can impact force-generating capacity and thus the potential to resist fatigue. Given that neuromuscular fatigue depends on interrelated factors, quantifying their independent effects on force-generating capacity is not possible in vivo. Computational models can provide insight into complex systems in which multiple inputs determine discrete outputs. However, few computational models to date have investigated neuromuscular fatigue by incorporating the multiple levels of neuromuscular function known to impact human in vivo function. To address this limitation, we present a computational model that predicts neural activation, biomechanical forces, intracellular metabolic perturbations and, ultimately, fatigue during repeated isometric contractions. This model was compared with metabolic and contractile responses to repeated activation using values reported in the literature. Once validated in this way, the model was modified to reflect age-related changes in neuromuscular function. Comparisons between initial and age-modified simulations indicated that the age-modified model predicted less fatigue during repeated isometric contractions, consistent with reports in the literature. Together, our simulations suggest that reduced glycolytic flux is the greatest contributor to the phenomenon of age-related fatigue resistance. In contrast, oxidative resynthesis of phosphocreatine between intermittent contractions and inherent buffering capacity had minimal impact on predicted fatigue during isometric contractions. The insights gained from these simulations cannot be achieved through traditional in vivo or in vitro experimentation alone.

Skeletal muscle ultrastructure and function in statin-tolerant individuals.

INTRODUCTION: Statins have well-known benefits on cardiovascular mortality, though up to 15% of patients experience side effects. With guidelines from the American Heart Association, American College of Cardiology, and American Diabetes Association expected to double the number of statin users, the overall incidence of myalgia and myopathy will increase. METHODS: We evaluated skeletal muscle structure and contractile function at the molecular, cellular, and whole tissue levels in 12 statin tolerant and 12 control subjects. RESULTS: Myosin isoform expression, fiber type distributions, single fiber maximal Ca(2+) -activated tension, and whole muscle contractile force were similar between groups. No differences were observed in myosin-actin cross-bridge kinetics in myosin heavy chain I or IIA fibers. CONCLUSIONS: We found no evidence for statin-induced changes in muscle morphology at the molecular, cellular, or whole tissue levels. Collectively, our data show that chronic statin therapy in healthy asymptomatic individuals does not promote deleterious myofilament structural or functional adaptations.

Chronic disuse and skeletal muscle structure in older adults: sex-specific differences and relationships to contractile function.

In older adults, we examined the effect of chronic muscle disuse on skeletal muscle structure at the tissue, cellular, organellar, and molecular levels and its relationship to muscle function. Volunteers with advanced-stage knee osteoarthritis (OA, n = 16) were recruited to reflect the effects of chronic lower extremity muscle disuse and compared with recreationally active controls (n = 15) without knee OA but similar in age, sex, and health status. In the OA group, quadriceps muscle and single-fiber cross-sectional area were reduced, with the largest reduction in myosin heavy chain IIA fibers. Myosin heavy chain IIAX fibers were more prevalent in the OA group, and their atrophy was sex-specific: men showed a reduction in cross-sectional area, and women showed no differences. Myofibrillar ultrastructure, myonuclear content, and mitochondrial content and morphology generally did not differ between groups, with the exception of sex-specific adaptations in subsarcolemmal (SS) mitochondria, which were driven by lower values in OA women. SS mitochondrial content was also differently related to cellular and molecular functional parameters by sex: greater SS mitochondrial content was associated with improved contractility in women but reduced function in men. Collectively, these results demonstrate sex-specific structural phenotypes at the cellular and organellar levels with chronic disuse in older adults, with novel associations between energetic and contractile systems.

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

Physical inactivity that accompanies ageing and disease may hasten disability by reducing skeletal muscle contractility. To characterize skeletal muscle functional adaptations to muscle disuse, we compared contractile performance at the molecular, cellular and whole­muscle levels in healthy active older men and women (n = 15) and inactive older men and women with advanced­stage, symptomatic knee osteoarthritis (OA) (n = 16). OA patients showed reduced (P < 0.01) knee extensor function. At the cellular level, single muscle fibre force production was reduced in OA patients in myosin heavy chain (MHC) I and IIA fibres (both P < 0.05) and differences in IIA fibres persisted after adjustments for fibre cross­sectional area (P < 0.05). Although no group differences in contractile velocity or power output were found for any fibre type, sex was found to modify the effect of OA, with a reduction in MHC IIA power output and a trend towards reduced shortening velocity in women, but increases in both variables in men (P < 0.05 and P = 0.07, respectively). At the molecular level, these adaptations in MHC IIA fibre function were explained by sex­specific differences (P ≤ 0.05) in myosin­actin cross­bridge kinetics. Additionally, cross­bridge kinetics were slowed in MHC I fibres in OA patients (P < 0.01), attributable entirely to reductions in women with knee OA (P < 0.05), a phenotype that could be reproduced in vitro by chemical modification of protein thiol residues. Our results identify molecular and cellular functional adaptations in skeletal muscle that may contribute to reduced physical function with knee OA­associated muscle disuse, with sex­specific differences that may explain a greater disposition towards disability in women.

Muscle weakness, fatigue, and torque variability: effects of age and mobility status.

INTRODUCTION: Whereas deficits in muscle function, particularly power production, develop in old age and are risk factors for mobility impairment, a complete understanding of muscle fatigue during dynamic contractions is lacking. We tested hypotheses related to torque-producing capacity, fatigue resistance, and variability of torque production during repeated maximal contractions in healthy older, mobility-impaired older, and young women. METHODS: Knee extensor fatigue (decline in torque) was measured during 4 min of dynamic contractions. Torque variability was characterized using a novel 4-component logistic regression model. RESULTS: Young women produced more torque at baseline and during the protocol than older women (P < 0.001). Although fatigue did not differ between groups (P = 0.53), torque variability differed by group (P = 0.022) and was greater in older impaired compared with young women (P = 0.010). CONCLUSIONS: These results suggest that increased torque variability may combine with baseline muscle weakness to limit function, particularly in older adults with mobility impairments.

Skeletal muscle protein metabolism in human heart failure.

PURPOSE OF REVIEW: This 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 FINDINGS: Advanced 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). SUMMARY: Although 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.

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.

Maintenance of skeletal muscle function following reduced daily physical activity in healthy older adults: a pilot trial.

Older adults can experience periods of inactivity related to disease or illness, which can hasten the development of physical disability, in part, through reductions in skeletal muscle strength and power. To date no study has characterized adaptations in skeletal muscle physical function in response to reduced daily physical activity. Participants (15 men, aged 69 ± 2 years; 15 women, aged 68 ± 4 years) restricted their daily steps (<750 steps/day) while being energy restricted (-500 kcal/day) for 2 weeks before returning to normal activity levels during recovery (RC; 1 week). Before and after each phase, measures of knee extensor isometric maximum voluntary contraction (MVC), time-to-peak torque, and physical function were performed and muscle biopsies were taken from a subset of participants. Following the energy restriction and step-reduction phase (ER+SR), MVC was reduced by 9.1 and 6.1 Nm in men and women, respectively (p = 0.02), which returned to baseline after RC in men, but not women (p = 0.046). Maximum isometric tension in MHC IIA fibres (p < 0.01) and maximum power production in MHC I and IIA (p = 0.05) were increased by 14%, 25%, and 10%, respectively, following ER+SR. Reductions in muscle strength could not be explained by changes in single muscle fibre function in a subsample (n = 9 men) of volunteers. These data highlight the resilience of physical function in healthy older men in the face of an acute period of ER+SR and demonstrate sex-based differences in the ability to recover muscle strength upon resumption of physical activity.

Age-related resistance to skeletal muscle fatigue is preserved during ischemia.

During voluntary contractions, the skeletal muscle of healthy older adults often fatigues less than that of young adults, a result that has been explained by relatively greater reliance on muscle oxidative metabolism in the elderly. Our aim was to investigate whether this age-related fatigue resistance was eliminated when oxidative metabolism was minimized via ischemia induced by cuff (220 mmHg). We hypothesized that 1) older men (n = 12) would fatigue less than young men (n = 12) during free-flow (FF) contractions; 2) both groups would fatigue similarly during ischemia; and 3) reperfusion would reestablish the fatigue resistance of the old. Subjects performed 6 min of intermittent, maximal voluntary isometric contractions of the ankle dorsiflexors under FF and ischemia-reperfusion (IR) conditions. Ischemia was maintained for the first 3 min of contractions, followed by rapid cuff deflation and reperfusion for 3 additional minutes of contractions. Central activation, peripheral activation, and muscle contractile properties were measured at 3 and 6 min of contractions. Older men fatigued less than young men during FF (P

Moderate-intensity resistance exercise alters skeletal muscle molecular and cellular structure and function in inactive older adults with knee osteoarthritis.

High-intensity resistance exercise (REX) training increases physical capacity, in part, by improving muscle cell size and function. Moderate-intensity REX, which is more feasible for many older adults with disease and/or disability, also increases physical function, but the mechanisms underlying such improvements are not understood. Therefore, we measured skeletal muscle structure and function from the molecular to the tissue level in response to 14 wk of moderate-intensity REX in physically inactive older adults with knee osteoarthritis (n = 17; 70 ± 1 yr). Although REX training increased quadriceps muscle cross-sectional area (CSA), average single-fiber CSA was unchanged because of reciprocal changes in myosin heavy chain (MHC) I and IIA fibers. Intermyofibrillar mitochondrial content increased with training because of increases in mitochondrial size in men, but not women, with no changes in subsarcolemmal mitochondria in either sex. REX increased whole muscle contractile performance similarly in men and women. In contrast, adaptations in single-muscle fiber force production per CSA (i.e., tension) and contractile velocity varied between men and women in a fiber type-dependent manner, with adaptations being explained at the molecular level by differential changes in myosin-actin cross-bridge kinetics and mechanics and single-fiber MHC protein expression. Our results are notable compared with studies of high-intensity REX because they show that the effects of moderate-intensity REX in older adults on muscle fiber size/structure and myofilament function are absent or modest. Moreover, our data highlight unique sex-specific adaptations due to differential cellular and subcellular structural and functional changes.NEW & NOTEWORTHY Moderate-intensity resistance training causes sex-specific adaptations in skeletal muscle structure and function at the cellular and molecular levels in inactive older adult men and women with knee osteoarthritis. However, these responses were minimal compared with high-intensity resistance training. Thus adjuncts to moderate-intensity training need to be developed to correct underlying cellular and molecular structural and functional deficits that are at the root of impaired physical function in this mobility-limited population.

Skeletal muscle fiber size and fiber type distribution in human cancer: Effects of weight loss and relationship to physical function.

BACKGROUND & AIMS: Cancer patients frequently experience weight loss, with negative consequences for functionality and prognosis. The extent to which muscle atrophy contributes to weight loss, however, is not clear, as few studies have directly measured muscle fiber morphology in cancer patients. METHODS: Whole body and regional tissue composition were measured, along with the cross-sectional area (CSA) and fiber type of mechanically-isolated, single muscle fibers, in 19 cancer patients (8 with a history of weight loss, 11 weight-stable) and 15 non-diseased controls. RESULTS: Whole body fat mass was reduced in cancer patients with a history of weight loss, but no differences in whole body or leg fat-free mass were apparent. In contrast, reductions (∼20%) in single muscle fiber CSA were found in both slow-twitch, myosin heavy chain (MHC) I and fast-twitch, MHC IIA fibers in both weight-stable patients and those with a history of weight loss. Fiber type distribution showed a shift towards a fast-twitch phenotype compared to controls, which may preserve muscle function in cancer patients despite atrophy, as positive relationships were found between the fractions of hybrid MHC IIAX and I/IIA fibers and 6-min walk performance. CONCLUSIONS: Our results suggest that, although not apparent from whole body or regional measurements, cancer is associated with reduced skeletal muscle fiber size independent of weight loss history and a shift towards fast-twitch fibers, phenotypes that resemble adaptations to muscle disuse.

Reduced rate of knee extensor torque development in older adults with knee osteoarthritis is associated with intrinsic muscle contractile deficits.

We examined the effect of knee osteoarthritis on the rate of torque development (RTD) of the knee extensors in older adults with advanced-stage knee osteoarthritis (OA; n=15) and recreationally-active controls (n=15) of similar age, sex and health status, as well as the relationship between RTD and the size and contractility of single muscle fibers. OA participants had lower RTD when expressed in absolute terms (Nm/ms). There were sex differences in peak RTD (P<0.05), with greater RTD in men, but no group by sex interaction effects for any variables. The lower RTD in OA versus controls was not explained by variation between groups in the fiber type admixture of the muscle, and was mitigated when RTD was normalized to peak torque (PT). In knee OA volunteers, we found strong correlations between the RTD expressed relative to PT and the velocity of contraction of single myosin heavy chain (MHC) I and IIA/X muscle fibers (r=0.652 and 0.862; both P<0.05) and power output of MHC I fibers (r=0.642; P<0.05). In controls, RTD relative to PT was related to fiber cross-sectional area of MHC IIA/X fibers (r=0.707; P<0.05), but not measures of single fiber contractile performance. To our knowledge, these results represent the first demonstration that variation in whole muscle contractile kinetics in patients with advanced-stage knee osteoarthritis and healthy older adults is related, in part, to the size and function of single muscle fibers.

Impact of muscle power and force on gait speed in disabled older men and women.

BACKGROUND: The purpose of this study was to explore the relationship between muscle power output at different external resistances and performance of functional tasks. The authors hypothesized that power at 40% skeletal muscle 1 repetition maximum (1RM), in which contraction velocity is high, would explain more of the variability in tasks such as level walking than would peak power or 1RM strength, in which contraction velocity is lower. METHODS: Participants were men and women (n = 48; ages 65-91 years) with physical disability as evidenced by 2 or more deficits on the Medical Outcomes Study Short Form physical function subscale or a score of 9 or less on the Established Populations for the Epidemiologic Studies of the Elderly short physical performance battery. Muscle strength (1RM) was measured using a bilateral leg press exercise, and power output was determined by selecting the highest power output from 6 different contraction velocities: 40%, 50%, 60%, 70%, 80%, and 90% 1RM. Functional performance tasks consisted of habitual gait velocity (HGV) and stair climb (SC) and chair rise (CR) performance. Separate linear regression models were fit for each of the 3 dependent variables (SC, CR, HGV) using 1RM strength, power at 70% 1RM, and power at 40% 1RM as independent variables. All models were adjusted for age, body mass, and sex. RESULTS: Lower extremity power at 70% and 40% 1RM demonstrated greater associations with SC and HGV than did 1RM strength, whereas power at 40% 1RM demonstrated similar or stronger associations with all functional tasks compared with 1RM strength. Power at 40% 1RM explained the same or more of the variability in SC (R(2) = .42 [regression coefficient = -.169 +/- .06] vs .43 [-.206 +/- .071]), CR (R(2) = .28 [-.154 +/- .057] vs .24 [-.152 + .070]) and HGV (R(2) = .59 [.214 + .37] vs .51 [.223 +/- .049]) compared with power at 70% 1RM. Power at 40% 1RM explained more of the variability in the lower intensity (HGV) compared with the higher intensity (SC or CR) functions. CONCLUSIONS: Power output at 40% of 1RM explained more of the variability in HGV than did power at 70% 1RM, suggesting that measures such as HGV that require a lower percentage of maximal strength to perform might be more sensitive to differences in contraction velocity. Because HGV is highly predictive of subsequent disability, future studies should evaluate the determinants of muscle power output at low external resistances.

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.

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.

A computational model of torque generation: neural, contractile, metabolic and musculoskeletal components.

The pathway of voluntary joint torque production includes motor neuron recruitment and rate-coding, sarcolemmal depolarization and calcium release by the sarcoplasmic reticulum, force generation by motor proteins within skeletal muscle, and force transmission by tendon across the joint. The direct source of energetic support for this process is ATP hydrolysis. It is possible to examine portions of this physiologic pathway using various in vivo and in vitro techniques, but an integrated view of the multiple processes that ultimately impact joint torque remains elusive. To address this gap, we present a comprehensive computational model of the combined neuromuscular and musculoskeletal systems that includes novel components related to intracellular bioenergetics function. Components representing excitatory drive, muscle activation, force generation, metabolic perturbations, and torque production during voluntary human ankle dorsiflexion were constructed, using a combination of experimentally-derived data and literature values. Simulation results were validated by comparison with torque and metabolic data obtained in vivo. The model successfully predicted peak and submaximal voluntary and electrically-elicited torque output, and accurately simulated the metabolic perturbations associated with voluntary contractions. This novel, comprehensive model could be used to better understand impact of global effectors such as age and disease on various components of the neuromuscular system, and ultimately, voluntary torque output.