Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Raising the intracellular [Ca2+] for 10 s at 23 degrees C abolished depolarization-induced force responses in mechanically skinned muscle fibres of toad and rat (half-maximal effect at 10 and 23 microM, respectively), without affecting the ability of caffeine or low [Mg2+] to open the ryanodine receptor (RyR)/Ca2+ release channels. Thus, excitation-contraction coupling was lost, even though the Ca2+ release channels were still functional. Coupling could not be restored in the duration of an experiment (up to 1 h). 2. The Ca(2+)-dependent uncoupling had a Q10 > 3.5, and was three times slower at pH 5.8 than at pH 7.1. Sr2+ caused similar uncoupling at twenty times higher concentration, but Mg2+, even at 10 mM, was ineffective. Uncoupling was not noticeably affected by removal of ATP or application of protein kinase or phosphatase inhibitors. 3. Confocal laser scanning microscopy showed that the transverse tubular system was sealed in its entirety in mechanically skinned fibres and that its integrity was maintained in uncoupled fibres. Electron microscopy revealed distorted or severed triad junctions and Z-line aberrations in uncoupled fibres. 4. Only when uncoupling was induced at a relatively slow rate (e.g. over 60 s with 2.5 microM Ca2+) could it be prevented by the protease inhibitor leupeptin (1 mM). Immunostaining of Western blots showed no evidence of proteolysis of the RyR, the alpha 1-subunit of dihydropyridine receptor (DHPR) or triadin in uncoupled fibres. 5. Fibres which, whilst intact, were stimulated repeatedly by potassium depolarization with simultaneous application of 30 mM caffeine showed reduced responsiveness after skinning to depolarization but not to caffeine. Rapid release of endogenous Ca2+, or raised [Ca2+] under conditions which minimized the loss of endogenous diffusible myoplasmic molecules from the skinned fibre, caused complete uncoupling. Taken together, these results suggest that Ca(2+)-dependent uncoupling can also occur in intact fibres. 6. This Ca(2+)-dependent loss of depolarization-induced Ca2+ release may play an important feedback role in muscle by stopping Ca2+ release in localized areas where it is excessive and may be responsible for long-lasting muscle fatigue after severe exercise, as well as contributing to muscle weakness in various dystrophies.
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PMID:Raised intracellular [Ca2+] abolishes excitation-contraction coupling in skeletal muscle fibres of rat and toad. 884 31

To examine mechanisms underlying force reduction after the onset of chronic low-frequency (10 Hz) stimulation (CLFS), we exposed rabbit tibialis anterior muscles to various durations of CLFS. To follow changes in isometric contractile properties and electromyographic (EMG) activity, we studied stimulated and contralateral muscles during a terminal test at 10 Hz for 10 min. In addition, activities and protein amounts of the sarcoplasmic reticulum Ca(2+)-ATPase, content of Na(+)-K(+)-ATPase, and expression patterns of triad junction components were examined. Force output and EMG amplitude declined abruptly soon after the onset of stimulation, suggesting refractoriness of a large fiber population. Although twitch force and to a lesser extent EMG activity gradually recovered after stimulation for 6 days and longer, the muscles exhibited profoundly altered properties, i.e., enhanced fatigue resistance, absence of twitch potentiation, and prolonged contraction and relaxation times. These changes were associated with significant increases in Na(+)-K(+)-ATPase concentration and significant decreases in Ca(2+)-ATPase, ryanodine receptor, dihydropyridine receptor, and triadin concentrations over the course of the 20 days of stimulation. Alterations in excitability, Ca2+ handling, and excitation-contraction coupling prior to changes in myofibrillar protein isoforms may thus be responsible for early functional alterations.
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PMID:Early functional and biochemical adaptations to low-frequency stimulation of rabbit fast-twitch muscle. 925 68

The activation and function of Ca(2+)-calmodulin-dependent kinase II (CaMKII) in contracting rat skeletal muscle was examined. The increase in autonomous activity and phosphorylation at Thr(287) of CaMKII of gastrocnemius muscle in response to contractions in situ was rapid and transient, peaking at 1-3 min, but reversed after 30 min of contractions. There was a positive correlation between CaMKII phosphorylation at Thr(287) and autonomous CaMKII activity. In contrast to the rapid and transient increase in autonomous CaMKII activity, the phosphorylation of the putative CaMKII substrate trisk95/triadin was rapid and sustained during contractions. There were no changes in CaMKII activity and phosphorylation or trisk95 phosphorylation in the resting contralateral muscles during stimulation. When fast-twitch muscles were contracted ex vivo, CaMKII inhibition resulted in a greater magnitude of fatigue as well as blunted CaMKII and trisk95 phosphorylation, identifying trisk95 as a physiological CaMKII substrate. In summary, skeletal muscle CaMKII activation was rapid and sustained during exercise/contraction and is mediated by factors within the contracting muscle, probably through allosteric activation via Ca(2+)-CaM. CaMKII may signal through trisk95 to modulate Ca(2+) release in fast-twitch rat skeletal muscle during exercise/contraction.
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PMID:Regulation and function of Ca2+-calmodulin-dependent protein kinase II of fast-twitch rat skeletal muscle. 1727 43

In the last decades the term Store-operated Ca2+ entry (SOCE) has been used in the scientific literature to describe an ubiquitous cellular mechanism that allows recovery of calcium (Ca2+) from the extracellular space. SOCE is triggered by a reduction of Ca2+ content (i.e. depletion) in intracellular stores, i.e. endoplasmic or sarcoplasmic reticulum (ER and SR). In skeletal muscle the mechanism is primarily mediated by a physical interaction between stromal interaction molecule-1 (STIM1), a Ca2+ sensor located in the SR membrane, and ORAI1, a Ca2+-permeable channel of external membranes, located in transverse tubules (TTs), the invaginations of the plasma membrane (PM) deputed to propagation of action potentials. It is generally accepted that in skeletal muscle SOCE is important to limit muscle fatigue during repetitive stimulation. We recently discovered that exercise promotes the assembly of new intracellular junctions that contains colocalized STIM1 and ORAI1, and that the presence of these new junctions increases Ca2+ entry via ORAI1, while improving fatigue resistance during repetitive stimulation. Based on these findings we named these new junctions Ca2+ Entry Units (CEUs). CEUs are dynamic organelles that assemble during muscle activity and disassemble during recovery thanks to the plasticity of the SR (containing STIM1) and the elongation/retraction of TTs (bearing ORAI1). Interestingly, similar structures described as SR stacks were previously reported in different mouse models carrying mutations in proteins involved in Ca2+ handling (calsequestrin-null mice; triadin and junctin null mice, etc.) or associated to microtubules (MAP6 knockout mice). Mutations in Stim1 and Orai1 (and calsequestrin-1) genes have been associated to tubular aggregate myopathy (TAM), a muscular disease characterized by: (a) muscle pain, cramping, or weakness that begins in childhood and worsens over time, and (b) the presence of large accumulations of ordered SR tubes (tubular aggregates, TAs) that do not contain myofibrils, mitochondria, nor TTs. Interestingly, TAs are also present in fast twitch muscle fibers of ageing mice. Several important issues remain un-answered: (a) the molecular mechanisms and signals that trigger the remodeling of membranes and the functional activation of SOCE during exercise are unclear; and (b) how dysfunctional SOCE and/or mutations in Stim1, Orai1 and calsequestrin (Casq1) genes lead to the formation of tubular aggregates (TAs) in aging and disease deserve investigation.
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PMID:Calcium entry units (CEUs): perspectives in skeletal muscle function and disease. 3281 18