Abstract
Muscle function depends on an adequate ATP supply to sustain the energy consumption associated with Ca(2+) cycling and actomyosin sliding during contraction. In this regulation of energy homeostasis, the creatine kinase (CK) circuit for high energy phosphoryl transfer between ATP and phosphocreatine plays an important role. We earlier established a functional connection between the activity of the CK system and Ca(2+) homeostasis during depolarization and contractile activity of muscle. Here, we show how CK activity is coupled to the kinetics of spontaneous and electrically induced Ca(2+) transients in the sarcoplasm of myotubes. Using the UV ratiometric Ca(2+) probe Indo-1 and video-rate confocal microscopy in CK-proficient and -deficient cultured cells, we found that spontaneous and electrically induced transients were dependent on ryanodine-sensitive Ca(2+) release channels, sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase pumps, extracellular calcium, and functional mitochondria in both cell types. However, at increasing sarcoplasmic Ca(2+) load (induced by electrical stimulation at 0.1, 1, and 10 Hz), the Ca(2+) removal rate and the amount of Ca(2+) released per transient were gradually reduced in CK-deficient (but not wild-type) myotubes. We conclude that the CK/phosphocreatine circuit is essential for efficient delivery of ATP to the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase pumps and thereby directly influences sarcoplasmic reticulum refilling and the kinetics of the sarcoplasmic Ca(2+) signals.
Highlights
Ionic Ca2ϩ regulates numerous cellular processes such as contraction, synaptic transmission, gene expression, metabolism, and cell death [1]
Various studies point to a direct involvement of creatine kinase (CK) in optimization of sarcoplasmic/endoplasmic reticulum Ca2ϩ-ATPase (SERCA) function and calcium homeostasis in skeletal muscle [8, 21,22,23], suggesting a direct link between regulation of appropriate ATP/ADP ratios and Ca2ϩ handling
As far as contractile properties are concerned, speed of muscle contraction and relaxation critically depend on the spatial arrangement of components belonging to the Ca2ϩ handling apparatus
Summary
Ionic Ca2ϩ regulates numerous cellular processes such as contraction, synaptic transmission, gene expression, metabolism, and cell death [1]. Ca2ϩ is a key regulator of contractile activity and glycolytic (activation of phosphorylase) and mitochondrial (activation of Ca2ϩ-sensitive dehydrogenases) ATP production [2, 3]. This is especially important during cycles of repetitive muscle contractions, when. Various studies point to a direct involvement of CK in optimization of SERCA function and calcium homeostasis in skeletal muscle [8, 21,22,23], suggesting a direct link between regulation of appropriate (local) ATP/ADP ratios and Ca2ϩ handling. To obtain a better understanding of this connection and its coupling to different Ca2ϩ signaling pathways, we need a more detailed picture of amplitude and frequency behavior of
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