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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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2.
Hypercontractile Esophagus From Pathophysiology to Management: Proceedings of the Pisa Symposium.
de Bortoli, N, Gyawali, PC, Roman, S, Tolone, S, Sifrim, D, Tutuian, R, Penagini, R, Pandolfino, JE, Savarino, EV
The American journal of gastroenterology. 2021;(2):263-273
Abstract
Hypercontractile esophagus (HE) is a heterogeneous major motility disorder diagnosed when ≥20% hypercontractile peristaltic sequences (distal contractile integral >8,000 mm Hg*s*cm) are present within the context of normal lower esophageal sphincter (LES) relaxation (integrated relaxation pressure < upper limit of normal) on esophageal high-resolution manometry (HRM). HE can manifest with dysphagia and chest pain, with unclear mechanisms of symptom generation. The pathophysiology of HE may entail an excessive cholinergic drive with temporal asynchrony of circular and longitudinal muscle contractions; provocative testing during HRM has also demonstrated abnormal inhibition. Hypercontractility can be limited to the esophageal body or can include the LES; rarely, the process is limited to the LES. Hypercontractility can sometimes be associated with esophagogastric junction (EGJ) outflow obstruction and increased muscle thickness. Provocative tests during HRM can increase detection of HE, reproduce symptoms, and predict delayed esophageal emptying. Regarding therapy, an empiric trial of a proton pump inhibitor, should be first considered, given the overlap with gastroesophageal reflux disease. Calcium channel blockers, nitrates, and phosphodiesterase inhibitors have been used to reduce contraction vigor but with suboptimal symptomatic response. Endoscopic treatment with botulinum toxin injection or pneumatic dilation is associated with variable response. Per-oral endoscopic myotomy may be superior to laparoscopic Heller myotomy in relieving dysphagia, but available data are scant. The presence of EGJ outflow obstruction in HE discriminates a subset of patients who may benefit from endoscopic treatment targeting the EGJ.
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3.
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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Abstract
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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4.
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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Abstract
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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Vitamin D and Skeletal Muscle: Emerging Roles in Development, Anabolism and Repair.
Girgis, CM
Calcified tissue international. 2020;(1):47-57
Abstract
This special issue article will focus on morphologic and functional roles of vitamin D in muscle, from strength to contraction to development and ageing and will characterise the controversy of VDR's expression in skeletal muscle, central to our understanding of vitamin D's effects on this tissue.
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Muscle fibre activation and fatigue with low-load blood flow restricted resistance exercise-An integrative physiology review.
Wernbom, M, Aagaard, P
Acta physiologica (Oxford, England). 2020;(1):e13302
Abstract
Blood flow-restricted resistance exercise (BFRRE) has been shown to induce increases in muscle size and strength, and continues to generate interest from both clinical and basic research points of view. The low loads employed, typically 20%-50% of the one repetition maximum, make BFRRE an attractive training modality for individuals who may not tolerate high musculoskeletal forces (eg, selected clinical patient groups such as frail old adults and patients recovering from sports injury) and/or for highly trained athletes who have reached a plateau in muscle mass and strength. It has been proposed that achieving a high degree of muscle fibre recruitment is important for inducing muscle hypertrophy with BFRRE, and the available evidence suggest that fatiguing low-load exercise during ischemic conditions can recruit both slow (type I) and fast (type II) muscle fibres. Nevertheless, closer scrutiny reveals that type II fibre activation in BFRRE has to date largely been inferred using indirect methods such as electromyography and magnetic resonance spectroscopy, while only rarely addressed using more direct methods such as measurements of glycogen stores and phosphocreatine levels in muscle fibres. Hence, considerable uncertainity exists about the specific pattern of muscle fibre activation during BFRRE. Therefore, the purpose of this narrative review was (1) to summarize the evidence on muscle fibre recruitment during BFRRE as revealed by various methods employed for determining muscle fibre usage during exercise, and (2) to discuss reported findings in light of the specific advantages and limitations associated with these methods.
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SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses.
Filippatos, TD, Liontos, A, Papakitsou, I, Elisaf, MS
Postgraduate medicine. 2019;(2):82-88
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors inhibit glucose re-absorption in the proximal renal tubules. Two trials have shown significant reductions of cardiovascular (CV) events with empagliflozin and canagliflozin, which could not be attributed solely to their antidiabetic effects. The aim of the review is the critical presentation of suggested mechanisms/hypotheses for the SGLT2 inhibitors' cardioprotection. The search of the literature revealed many possible cardioprotective mechanisms, because SGLT2 inhibitors (i) increase natriuresis and act as diuretics with unique properties leading to a reduction in preload and myocardial stretch (the diuretic hypothesis); (ii) decrease blood pressure and afterload (the blood pressure lowering hypothesis), (iii) favor the production of ketones, which can act as a 'superfuel' in the cardiac and renal tissue (the 'thrifty substrate' hypothesis), (iv) improve many metabolic variables (the metabolic effects hypothesis), (v) exert many anti-inflammatory effects (the anti-inflammatory effects hypothesis), (vi) can act through the angiotensin II type II receptors in the context of simultaneous renin-angiotensin-aldosterone-system (RAAS) blockade leading to vasodilation and positive inotropic effects (the RAAS hypothesis), (vii) directly decrease the activity of the upregulated in heart failure Na+-H+ exchanger in myocardial cells leading to restoration of mitochondrial calcium handling in cardiomyocytes (the sodium hypothesis). Additionally, some SGLT2 inhibitors exhibit also SGLT1 inhibitory action possibly resulting in an attenuation of oxidative stress in ischemic myocardium (the SGLT1 inhibition hypothesis). Thus, many mechanisms have been suggested (and possibly act cumulatively) for the cardioprotective effects of SGLT2 inhibitors.
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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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9.
An Exciting Couple.
Etlinger, JD
Journal of pediatric ophthalmology and strabismus. 2018;(3):149-150
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10.
Neurophysiological Mechanisms Underpinning Stretch-Induced Force Loss.
Trajano, GS, Nosaka, K, Blazevich, AJ
Sports medicine (Auckland, N.Z.). 2017;(8):1531-1541
Abstract
It is well known that prolonged passive muscle stretch reduces maximal muscle force production. There is a growing body of evidence suggesting that adaptations occurring within the nervous system play a major role in this stretch-induced force reduction. This article reviews the existing literature, and some new evidence, regarding acute neurophysiological changes in response to passive muscle stretching. We discuss the possible contribution of supra-spinal and spinal structures to the force reduction after passive muscle stretch. In summary, based on the recent evidence reviewed we propose a new hypothesis that a disfacilitation occurring at the motoneuronal level after passive muscle stretch is a major factor affecting the neural efferent drive to the muscle and, subsequently, its ability to produce maximal force.