Coupled Ca
 2+
 /H
 +
 transport by cytoplasmic buffers regulates local Ca
 2+
 and H
 +
 ion signaling

Swietach, Pawel; Youm, Jae Boum; Saegusa, Noriko; Leem, Chae Hun; Spitzer, Kenneth W.; Vaughan‐Jones, Richard D.

doi:10.1073/pnas.1222433110

Cited by 92 publications

(87 citation statements)

References 43 publications

(47 reference statements)

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“…Alternatively, the decrease in HRT may be associated with the Ca 2+ component of skeletal muscle relaxation speed, given that it has been proposed that Ca 2+ re-uptake by the sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) is the rate-limiting step in muscle relaxation (Gillis 1985; Dux 1993). The transfer of Ca 2+ into the SR lumen by the SERCA pump is accompanied by a counter-transport of H + out into the cytosol (Tran et al 2009), by acting on Ca 2+ -handling proteins directly or via other molecules, Ca 2+ signalling can be inhibited or excited (Swietach et al 2013). The presence of carnosine has already been shown to improve isolated rat heart muscle contraction and increases free intracellular Ca 2+ concentrations (Zaloga et al 1996).…”

Section: Discussionmentioning

confidence: 99%

β-alanine supplementation improves in-vivo fresh and fatigued skeletal muscle relaxation speed

et al. 2017

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PurposeIn fresh muscle, supplementation with the rate-limiting precursor of carnosine, β-alanine (BA), results in a decline in muscle half-relaxation time (HRT) potentially via alterations to calcium (Ca2+) handling. Accumulation of hydrogen cation (H+) has been shown to impact Ca2+ signalling during muscular contraction, carnosine has the potential to serve as a cytoplasmic regulator of Ca2+ and H+ coupling, since it binds to both ions. The present study examined the effect of BA supplementation on intrinsic in-vivo isometric knee extensor force production and muscle contractility in both fresh and fatigued human skeletal muscle assessed during voluntary and electrically evoked (nerve and superficial muscle stimulation) contractions.MethodsTwenty-three males completed two experimental sessions, pre- and post- 28 day supplementation with 6.4 g.day−1 of BA (n = 12) or placebo (PLA; n = 11). Isometric force was recorded during a series of voluntary and electrically evoked knee extensor contractions.ResultsBA supplementation had no effect on voluntary or electrically evoked isometric force production, or twitch electromechanical delay and time-to-peak tension. There was a significant decline in muscle HRT in fresh and fatigued muscle conditions during both resting (3 ± 13%; 19 ± 26%) and potentiated (1 ± 15%; 2 ± 20%) twitch contractions.ConclusionsThe mechanism for reduced HRT in fresh and fatigued skeletal muscle following BA supplementation is unclear. Due to the importance of muscle relaxation on total energy consumption, especially during short, repeated contractions, BA supplementation may prove to be beneficial in minimising contractile slowing induced by fatigue.Trial registrationThe trial is registered with Clinicaltrials.gov, ID number NCT02819505.

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Section: Discussionmentioning

confidence: 99%

β-alanine supplementation improves in-vivo fresh and fatigued skeletal muscle relaxation speed

et al. 2017

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“…8a) in our experimental condition, modifications proposed by Saegusa et al [22] were all scaled down to 1/5 and were applied to our simulation. The increased intracellular H + is also known to raise intracellular Ca 2+ by unloading Ca 2+ from Ca 2+ -buffering proteins (coupled Ca 2+ /H + transport by cytoplasmic buffers regulates local Ca 2+ and H + ion signaling [23]). In our simulation, the ability of increased intracellular H + to unload Ca 2+ from Ca 2+ -buffering proteins was embodied by assuming it reduces Ca 2+ on rates for TnC.…”

Section: Discussionmentioning

confidence: 99%

Cardiac inotropy, lusitropy, and Ca2+ handling with major metabolic substrates in rat heart

Zhao

Youm

Wang

et al. 2016

Pflugers Arch - Eur J Physiol

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Fatty acid (FA)-dependent oxidation is the predominant process for energy supply in normal heart. Impaired FA metabolism and metabolic insufficiency underlie the failing of the myocardium. So far, FA metabolism in normal cardiac physiology and heart failure remains undetermined. Here, we evaluate the mechanisms of FA and major metabolic substrates (termed NF) on the contraction, relaxation, and Ca2+ handling in rat left ventricular (LV) myocytes. Our results showed that NF significantly increased myocyte contraction and facilitated relaxation. Moreover, NF increased the amplitudes of diastolic and systolic Ca2+ transients ([Ca2+]i), abbreviated time constant of [Ca2+]i decay (tau), and prolonged the peak duration of [Ca2+]i. Whole-cell patch-clamp experiments revealed that NF increased Ca2+ influx via L-type Ca2+ channels (LTCC, ICa-integral) and prolonged the action potential duration (APD). Further analysis revealed that NF shifted the relaxation phase of sarcomere lengthening vs. [Ca2+]i trajectory to the right and increased [Ca2+]i for 50 % of sarcomere relengthening (EC50), suggesting myofilament Ca2+ desensitization. Butanedione monoxime (BDM), a myosin ATPase inhibitor that reduces myofilament Ca2+ sensitivity, abolished the NF-induced enhancement of [Ca2+]i amplitude and the tau of [Ca2+]i decay, indicating the association of myofilament Ca2+ desensitization with the changes in [Ca2+]i profile in NF. NF reduced intracellular pH ([pHi]). Increasing [pH]i buffer capacity with HCO3/CO2 attenuated Δ [pH]i and reversed myofilament Ca2+ desensitization and Ca2+ handling in NF. Collectively, greater Ca2+ influx through LTCCs and myofilament Ca2+ desensitization, via reducing [pH]i, are likely responsible for the positive inotropic and lusitropic effects of NF. Computer simulation recapitulated the effects of NF.Electronic supplementary materialThe online version of this article (doi:10.1007/s00424-016-1892-8) contains supplementary material, which is available to authorized users.

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“…Our recent findings challenge this notion by demonstrating that a class of soluble molecules can mediate uphill Ca 2+ transport driven by a cytoplasmic [H + ] ([H + ] i ) gradient but without a membrane (Swietach et al . ). The basis for this novel paradigm in ion exchange is the mechanism of H + ion transport in cytoplasm.…”

Section: The Signalling Ion Calcium Is Highly Compartmentalized In Camentioning

confidence: 97%

Pumping Ca²⁺ up H⁺ gradients: a Ca²⁺–H⁺ exchanger without a membrane

Swietach

Leem

Spitzer

et al. 2014

The Journal of Physiology

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Coupled Ca ²⁺ /H ⁺ transport by cytoplasmic buffers regulates local Ca ²⁺ and H ⁺ ion signaling

Cited by 92 publications

References 43 publications

β-alanine supplementation improves in-vivo fresh and fatigued skeletal muscle relaxation speed

β-alanine supplementation improves in-vivo fresh and fatigued skeletal muscle relaxation speed

Cardiac inotropy, lusitropy, and Ca2+ handling with major metabolic substrates in rat heart

Pumping Ca²⁺ up H⁺ gradients: a Ca²⁺–H⁺ exchanger without a membrane

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Coupled Ca 2+ /H + transport by cytoplasmic buffers regulates local Ca 2+ and H + ion signaling

Cited by 92 publications

References 43 publications

β-alanine supplementation improves in-vivo fresh and fatigued skeletal muscle relaxation speed

β-alanine supplementation improves in-vivo fresh and fatigued skeletal muscle relaxation speed

Cardiac inotropy, lusitropy, and Ca2+ handling with major metabolic substrates in rat heart

Pumping Ca2+ up H+ gradients: a Ca2+–H+ exchanger without a membrane

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Coupled Ca ²⁺ /H ⁺ transport by cytoplasmic buffers regulates local Ca ²⁺ and H ⁺ ion signaling

Pumping Ca²⁺ up H⁺ gradients: a Ca²⁺–H⁺ exchanger without a membrane