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.
The force response of activated striated muscle to length perturbations includes the so-called C-process, which has been considered the frequency domain representation of the fast single-exponential force decay after a length step (phases 1 and 2). The underlying molecular mechanisms of this phenomenon, however, are still the subject of various hypotheses. In this study, we derived analytical expressions and created a corresponding computer model to describe the consequences of independent acto-myosin cross-bridges characterized solely by 1), intermittent periods of attachment (t(att)) and detachment (t(det)), whose values are stochastically governed by independent probability density functions; and 2), a finite Hookian stiffness (k(stiff)) effective only during periods of attachment. The computer-simulated force response of 20,000 (N) cross-bridges making up a half-sarcomere (F(hs)(t)) to sinusoidal length perturbations (L(hs)(t)) was predicted by the analytical expression in the frequency domain, (F(hs)(omega)/L(hs)(omega))=(t(att)/t(cycle))Nk(stiff)(iomega/(t(att)(-1)+iomega)), where t(att) = mean value of t(att), t(cycle) = mean value of t(att) + t(det), k(stiff) = mean stiffness, and omega = 2pi x frequency of perturbation. The simulated force response due to a length step (L(hs)) was furthermore predicted by the analytical expression in the time domain, F(hs)(t)=(t(att)/t(cycle))Nk(stiff)L(hs)e(-t/t(att)). The forms of these analytically derived expressions are consistent with expressions historically used to describe these specific characteristics of a force response and suggest that the cycling of acto-myosin cross-bridges and their associated stiffnesses are responsible for the C-process and for phases 1 and 2. The rate constant 2pic, i.e., the frequency parameter of the historically defined C-process, is shown here to be equal to t(att)(-1). Experimental results from activated cardiac muscle examined at different temperatures and containing predominately alpha- or beta-myosin heavy chain isoforms were found to be consistent with the above interpretation.
Skeletal muscle function is impaired in heart failure patients due, in part, to loss of myofibrillar protein content, in particular myosin. In the present study, we utilized small-amplitude sinusoidal analysis for the first time in single human skeletal muscle fibres to measure muscle mechanics, including cross-bridge kinetics, to determine if heart failure further impairs contractile performance by altering myofibrillar protein function. Patients with chronic heart failure (n = 9) and controls (n = 6) were recruited of similar age and physical activity to diminish the potentially confounding effects of ageing and muscle disuse. Patients showed decreased cross-bridge kinetics in myosin heavy chain (MHC) I and IIA fibres, partially due to increased myosin attachment time (t on ). The increased t on compensated for myosin protein loss previously found in heart failure patients by increasing the fraction of the total cycle time myosin is bound to actin, resulting in a similar number of strongly bound cross-bridges in patients and controls. Accordingly, isometric tension did not differ between patients and controls in MHC I or IIA fibres. Patients also had decreased calcium sensitivity in MHC IIA fibres and alterations in the viscoelastic properties of the lattice structure of MHC I and IIA fibres. Collectively, these results show that heart failure alters skeletal muscle contraction at the level of the myosin-actin cross-bridge, leading to changes in muscle mechanics which could contribute to impaired muscle function. Additionally, we uncovered a unique kinetic property of MHC I fibres, a potential indication of two distinct populations of cross-bridges, which may have important physiological consequences. Abbreviations A, A-process magnitude; B, B-process magnitude; C, C-process magnitude; CSA, cross-sectional area; E e , elastic modulus; E v , viscous modulus; f , frequency of the length perturbations; F, force; F/CSA, tension; HF, heart failure; k, A-process unitless exponent; L, fibre length; L amp , length oscillation amplitude; MHC, myosin heavy chain; MLC, myosin light chain; n, Hill coefficient; P i , phosphate; t, time needed to perform length perturbations; t on , average myosin attachment time; t 3 , time from the start of stretch activation to the peak tension; Y (ω), complex modulus at peak calcium activation; L, fibre length change; L/L, fibre strain; ω, 2π × the frequency of the length perturbation; 2πb, B-process characteristic rate; 2πc, C-process characteristic rate.
Key pointsr Muscle disuse that accompanies ageing and chronic disease may hasten physical disability by impairing skeletal muscle contractility.r 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.r 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.r 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.Abstract 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 whole-muscle levels in healthy active older men and women (n = 15) and inactive older men and women with advanced-stage, 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 cross-sectional 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 sex-specific differences (P ࣘ 0.05) in myosin-actin cross-bridge kinetics. Additionally, cross-bridge 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 OA-associated muscle disuse, with sex-specific differences that may explain a greater disposition towards disability in women. Abbreviations A, A-process magnitude; B, B-process magnitude; BMI, body mass index; C, C-process magnitude; CP, creatine phosphate; CPK, creatine phosphokinase; CSA, cross-sectional area; DTT, dithiothreitol; f, frequency of length pertu...
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 diagnosed with breast cancer, who were receiving adjuvant chemotherapy following tumor resection, and 12 non-diseased controls. Breast cancer patients showed reduced single muscle fiber cross-sectional area (CSA) and fractional content of both sub-sarcolemmal 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 muscle myotube cell cultures, supporting a role for chemotherapeutics in the atrophic and mitochondrial phenotypes. Additionally, concurrent treatment of myotubes with 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 CSA. 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.
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