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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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An Exciting Couple.
Etlinger, JD
Journal of pediatric ophthalmology and strabismus. 2018;(3):149-150
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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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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.
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Fatigue associated with prolonged graded running.
Giandolini, M, Vernillo, G, Samozino, P, Horvais, N, Edwards, WB, Morin, JB, Millet, GY
European journal of applied physiology. 2016;(10):1859-73
Abstract
Scientific experiments on running mainly consider level running. However, the magnitude and etiology of fatigue depend on the exercise under consideration, particularly the predominant type of contraction, which differs between level, uphill, and downhill running. The purpose of this review is to comprehensively summarize the neurophysiological and biomechanical changes due to fatigue in graded running. When comparing prolonged hilly running (i.e., a combination of uphill and downhill running) to level running, it is found that (1) the general shape of the neuromuscular fatigue-exercise duration curve as well as the etiology of fatigue in knee extensor and plantar flexor muscles are similar and (2) the biomechanical consequences are also relatively comparable, suggesting that duration rather than elevation changes affects neuromuscular function and running patterns. However, 'pure' uphill or downhill running has several fatigue-related intrinsic features compared with the level running. Downhill running induces severe lower limb tissue damage, indirectly evidenced by massive increases in plasma creatine kinase/myoglobin concentration or inflammatory markers. In addition, low-frequency fatigue (i.e., excitation-contraction coupling failure) is systematically observed after downhill running, although it has also been found in high-intensity uphill running for different reasons. Indeed, low-frequency fatigue in downhill running is attributed to mechanical stress at the interface sarcoplasmic reticulum/T-tubule, while the inorganic phosphate accumulation probably plays a central role in intense uphill running. Other fatigue-related specificities of graded running such as strategies to minimize the deleterious effects of downhill running on muscle function, the difference of energy cost versus heat storage or muscle activity changes in downhill, level, and uphill running are also discussed.
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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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Abstract
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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8.
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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Abstract
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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Structural and functional interactions within ryanodine receptor.
Seidel, M, Lai, FA, Zissimopoulos, S
Biochemical Society transactions. 2015;(3):377-83
Abstract
The ryanodine receptor/Ca2+ release channel plays a pivotal role in skeletal and cardiac muscle excitation-contraction coupling. Defective regulation leads to neuromuscular disorders and arrhythmogenic cardiac disease. This mini-review focuses on channel regulation through structural intra- and inter-subunit interactions and their implications in ryanodine receptor pathophysiology.