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Age-Related Skeletal Muscle Dysfunction Is Aggravated by Obesity: An Investigation of Contractile Function, Implications and Treatment.
Tallis, J, Shelley, S, Degens, H, Hill, C
Biomolecules. 2021;(3)
Abstract
Obesity is a global epidemic and coupled with the unprecedented growth of the world's older adult population, a growing number of individuals are both old and obese. Whilst both ageing and obesity are associated with an increased prevalence of chronic health conditions and a substantial economic burden, evidence suggests that the coincident effects exacerbate negative health outcomes. A significant contributor to such detrimental effects may be the reduction in the contractile performance of skeletal muscle, given that poor muscle function is related to chronic disease, poor quality of life and all-cause mortality. Whilst the effects of ageing and obesity independently on skeletal muscle function have been investigated, the combined effects are yet to be thoroughly explored. Given the importance of skeletal muscle to whole-body health and physical function, the present study sought to provide a review of the literature to: (1) summarise the effect of obesity on the age-induced reduction in skeletal muscle contractile function; (2) understand whether obesity effects on skeletal muscle are similar in young and old muscle; (3) consider the consequences of these changes to whole-body functional performance; (4) outline important future work along with the potential for targeted intervention strategies to mitigate potential detrimental effects.
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MyBP-C: one protein to govern them all.
Heling, LWHJ, Geeves, MA, Kad, NM
Journal of muscle research and cell motility. 2020;(1):91-101
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The heart is an extraordinarily versatile pump, finely tuned to respond to a multitude of demands. Given the heart pumps without rest for decades its efficiency is particularly relevant. Although many proteins in the heart are essential for viability, the non-essential components can attract numerous mutations which can cause disease, possibly through alterations in pumping efficiency. Of these, myosin binding protein C is strongly over-represented with ~ 40% of all known mutations in hypertrophic cardiomyopathy. Therefore, a complete understanding of its molecular function in the cardiac sarcomere is warranted. In this review, we revisit contemporary and classical literature to clarify both the current standing of this fast-moving field and frame future unresolved questions. To date, much effort has been directed at understanding MyBP-C function on either thick or thin filaments. Here we aim to focus questions on how MyBP-C functions at a molecular level in the context of both the thick and thin filaments together. A concept that emerges is MyBP-C acts to govern interactions on two levels; controlling myosin access to the thin filament by sequestration on the thick filament, and controlling the activation state and access of myosin to its binding sites on the thin filament. Such affects are achieved through directed interactions mediated by phosphorylation (of MyBP-C and other sarcomeric components) and calcium.
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Troponin structure and function: a view of recent progress.
Marston, S, Zamora, JE
Journal of muscle research and cell motility. 2020;(1):71-89
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The molecular mechanism by which Ca2+ binding and phosphorylation regulate muscle contraction through Troponin is not yet fully understood. Revealing the differences between the relaxed and active structure of cTn, as well as the conformational changes that follow phosphorylation has remained a challenge for structural biologists over the years. Here we review the current understanding of how Ca2+, phosphorylation and disease-causing mutations affect the structure and dynamics of troponin to regulate the thin filament based on electron microscopy, X-ray diffraction, NMR and molecular dynamics methodologies.
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Electron Microscopic Recording of the Power and Recovery Strokes of Individual Myosin Heads Coupled with ATP Hydrolysis: Facts and Implications.
Sugi, H, Chaen, S, Akimoto, T
International journal of molecular sciences. 2018;(5)
Abstract
The most straightforward way to get information on the performance of individual myosin heads producing muscle contraction may be to record their movement, coupled with ATP hydrolysis, electron-microscopically using the gas environmental chamber (EC). The EC enables us to visualize and record ATP-induced myosin head movement in hydrated skeletal muscle myosin filaments. When actin filaments are absent, myosin heads fluctuate around a definite neutral position, so that their time-averaged mean position remains unchanged. On application of ATP, myosin heads are found to move away from, but not towards, the bare region, indicating that myosin heads perform a recovery stroke (average amplitude, 6 nm). After exhaustion of ATP, myosin heads return to their neutral position. In the actin⁻myosin filament mixture, myosin heads form rigor actin myosin linkages, and on application of ATP, they perform a power stroke by stretching adjacent elastic structures because of a limited amount of applied ATP ≤ 10 µM. The average amplitude of the power stroke is 3.3 nm and 2.5 nm at the distal and the proximal regions of the myosin head catalytic domain (CAD), respectively. The power stroke amplitude increases appreciably at low ionic strength, which is known to enhance Ca2+-activated force in muscle. In both the power and recovery strokes, myosin heads return to their neutral position after exhaustion of ATP.
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Diversity and plasticity in signaling pathways that regulate smooth muscle responsiveness: Paradigms and paradoxes for the myosin phosphatase, the master regulator of smooth muscle contraction.
Eto, M, Kitazawa, T
Journal of smooth muscle research = Nihon Heikatsukin Gakkai kikanshi. 2017;(0):1-19
Abstract
A hallmark of smooth muscle cells is their ability to adapt their functions to meet temporal and chronic fluctuations in their demands. These functions include force development and growth. Understanding the mechanisms underlying the functional plasticity of smooth muscles, the major constituent of organ walls, is fundamental to elucidating pathophysiological rationales of failures of organ functions. Also, the knowledge is expected to facilitate devising innovative strategies that more precisely monitor and normalize organ functions by targeting individual smooth muscles. Evidence has established a current paradigm that the myosin light chain phosphatase (MLCP) is a master regulator of smooth muscle responsiveness to stimuli. Cellular MLCP activity is negatively and positively regulated in response to G-protein activation and cAMP/cGMP production, respectively, through the MYPT1 regulatory subunit and an endogenous inhibitor protein named CPI-17. In this article we review the outcomes from two decade of research on the CPI-17 signaling and discuss emerging paradoxes in the view of signaling pathways regulating smooth muscle functions through MLCP.
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A reduced activity model: a relevant tool for the study of ageing muscle.
Perkin, O, McGuigan, P, Thompson, D, Stokes, K
Biogerontology. 2016;(3):435-47
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Skeletal muscle mass is in a constant state of turnover, and atrophy is the result of a shift in the balance of muscle protein synthesis and breakdown resulting in net muscle protein loss. Total disuse of skeletal muscle quickly leads to muscle atrophy and loss of strength, and this has been repeatedly demonstrated in studies employing bed rest and lower limb immobilisation methodologies in young healthy participants. Fewer studies have focused on older participants (>65 years of age), but those that have provide evidence that advancing age brings increased vulnerability to rapid and marked loss of muscle size and strength during period of total muscle unloading. Increased systemic inflammation and reduced protein synthetic responses to protein feeding and muscle contraction might influence the severity of muscle protein loss during periods of total unloading compared with younger individuals. Less extreme reductions in muscle loading (e.g., 2 weeks of reducing daily ambulation to <1500 steps/day) have also been shown to result in decreases in muscle mass. This step-reduction model may be more relevant than total bed rest or limb immobilisation for examining real-world scenarios that present a physiological challenge to the maintenance of skeletal muscle mass in older individuals.
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Problems with extracellular recording of electrical activity in gastrointestinal muscle.
Sanders, KM, Ward, SM, Hennig, GW
Nature reviews. Gastroenterology & hepatology. 2016;(12):731-741
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Abstract
Motility patterns of the gastrointestinal tract are important for efficient processing of nutrients and waste. Peristalsis and segmentation are based on rhythmic electrical slow waves that generate the phasic contractions fundamental to gastrointestinal motility. Slow waves are generated and propagated actively by interstitial cells of Cajal (ICC), and these events conduct to smooth muscle cells to elicit excitation-contraction coupling. Extracellular electrical recording has been utilized to characterize slow-wave generation and propagation and abnormalities that might be responsible for gastrointestinal motility disorders. Electrode array recording and digital processing are being used to generate data for models of electrical propagation in normal and pathophysiological conditions. Here, we discuss techniques of extracellular recording as applied to gastrointestinal organs and how mechanical artefacts might contaminate these recordings and confound their interpretation. Without rigorous controls for movement, current interpretations of extracellular recordings might ascribe inaccurate behaviours and electrical anomalies to ICC networks and gastrointestinal muscles, bringing into question the findings and validity of models of gastrointestinal electrophysiology developed from these recordings.
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The effect of metabolic alkalosis on central and peripheral mechanisms associated with exercise-induced muscle fatigue in humans.
Siegler, JC, Marshall, P
Experimental physiology. 2015;(5):519-30
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What is the central question of this study? Does metabolic alkalosis affect central and peripheral mechanisms associated with exercise-induced muscle fatigue in humans? What is the main finding and its importance? Inducing metabolic alkalosis before exercise preserved voluntary activation, but not muscle excitation, after a 2 min maximal voluntary contraction (MVC) followed by ischaemia. An effect of pH was also observed in maximal rates of torque development, where alkalosis mitigated the reduction in maximal rates of torque development after the initial 2 min MVC. For the first time, these results demonstrate a differential effect of pH on voluntary activation as well as maximal rates of torque development after sustained, maximal voluntary knee extension in humans. The increased concentration of protons during fatiguing exercise may contribute to increased activation of group III and IV afferents and subsequently reduced central drive, but this has yet to be confirmed in exercising humans. Here, we determined whether inducing metabolic alkalosis differentially affects descending central drive after fatiguing exercise and whether this effect may, in part, be explained by attenuating group III and IV afferent firing. Eleven men performed a maximal 2 min voluntary knee extension (MVC) followed by a 2 min rest and subsequent 1 min MVC with an occlusive cuff either in placebo [PLA; 0.3 g (kg body weight)(-1) calcium carbonate] or alkalosis conditions [ALK; 0.3 g (kg body weight)(-1) sodium bicarbonate]. Femoral nerve stimulation was applied before exercise, after the 2 min MVC and at 40-60 s intervals throughout the remainder of the protocol to explore central and peripheral mechanisms associated with reductions in maximal force and rate of torque development. Although voluntary activation declined to a similar extent after the 2 min MVC, during the ischaemic period voluntary activation was higher during ALK (PLA, 57 ± 8%; ALK, 76 ± 5%). Maximal voluntary torque declined at similar rates during the task (203 ± 19 N m), but maximal rate of torque development was significantly higher in the ALK conditions after the 2 min MVC (mean difference of 177 ± 60 N m s(-1) ). These results demonstrate the effect of pH on voluntary activation as well as maximal rates of torque development after sustained, maximal voluntary knee extension in humans.
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Renewed avenues through exercise muscle contractility and inflammatory status.
Zanchi, NE, Almeida, FN, Lira, FS, Rosa Neto, JC, Nicastro, H, da Luz, CR, de Siqueira Filho, MA, Felitti, V, Vainzof, M, Seelaender, M, et al
TheScientificWorldJournal. 2012;:584205
Abstract
Physical inactivity leads to the accumulation of visceral fat and, consequently, to the activation of a network of inflammatory pathways which may promote development of insulin resistance, atherosclerosis, neurodegeneration, and tumour growth. These conditions belong to the "diseasome of physical inactivity". In contrast, the protective effect of regular exercise against diseases associated with chronic inflammation may to some extent be ascribed to an anti-inflammatory effect. The so called "acute exercise threshold", the complex mixture of several variables involved in exercise, such as type, volume, frequency, and intensity range is capable of inducing positive physiological adaptations and has been specifically addressed in the recent literature. The major concern is related to the level of the threshold: "exercise training shifts from a therapeutic adaptive intervention to one with potential pathological consequences". Nonetheless, if the mechanical stimulus is too weak to disrupt cellular homeostasis, training adaptations will not occur. Answering these questions could present practical applications, especially during inflammatory diseases associated with detrimental muscle effects and could theoretically constitute a "new" therapeutic approach to treat/improve an inflammatory state. This paper aims to describe specific data from the literature regarding the effects of exercise on inflammatory diseases in order to promote a more sophisticated perspective on the anti-inflammatory effects of exercise.
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Regulation of gastrointestinal motility--insights from smooth muscle biology.
Sanders, KM, Koh, SD, Ro, S, Ward, SM
Nature reviews. Gastroenterology & hepatology. 2012;(11):633-45
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Abstract
Gastrointestinal motility results from coordinated contractions of the tunica muscularis, the muscular layers of the alimentary canal. Throughout most of the gastrointestinal tract, smooth muscles are organized into two layers of circularly or longitudinally oriented muscle bundles. Smooth muscle cells form electrical and mechanical junctions between cells that facilitate coordination of contractions. Excitation-contraction coupling occurs by Ca(2+) entry via ion channels in the plasma membrane, leading to a rise in intracellular Ca(2+). Ca(2+) binding to calmodulin activates myosin light chain kinase; subsequent phosphorylation of myosin initiates cross-bridge cycling. Myosin phosphatase dephosphorylates myosin to relax muscles, and a process known as Ca(2+) sensitization regulates the activity of the phosphatase. Gastrointestinal smooth muscles are 'autonomous' and generate spontaneous electrical activity (slow waves) that does not depend upon input from nerves. Intrinsic pacemaker activity comes from interstitial cells of Cajal, which are electrically coupled to smooth muscle cells. Patterns of contractile activity in gastrointestinal muscles are determined by inputs from enteric motor neurons that innervate smooth muscle cells and interstitial cells. Here we provide an overview of the cells and mechanisms that generate smooth muscle contractile behaviour and gastrointestinal motility.