Background: Patients with chronic renal failure may develop muscle weakness and fatigability due to disorders of skeletal muscle function, collectively known as the uremic myopathy. Cyclic adenosine diphosphate-ribose (cADPR), an endogenous metabolite of β-NAD+, activates Ca2+ release from intracellular stores in vertebrate and invertebrate cells. The current study investigated the possible role of cADPR in uremic myopathy. Methods: We have examined the effect of cADPR on myoplasmic resting Ca2+ concentration ([Ca2+]i) in skeletal muscle obtained from control subjects and uremic patients (UP). [Ca2+]i was measuredusing double-barreled Ca2+-selective microelectrodes in muscle fibers, prior to and after microinjections of cADPR. Results: Resting [Ca2+]i was elevated in UP fibers compared with fibers obtained from control subjects. Removal of extracellular Ca2+, or incubation of cells with nifedipine, did not modify [Ca2+]i in UP or control fibers. Microinjection of cADPR produced an elevation of [Ca2+]i in both groups of cells. This elevation was not mediated by Ca2+ influx, or inhibited by heparin or ryanodine. [cADPR]i was determined to be higher in muscle fibers from UP compared to those from the control subjects. Incubation of cells with 8-bromo-cADPR, a cADPR antagonist, partially reduced [Ca2+]i in UP muscle fibers and blocked the cADPR-elicited elevation in [Ca2+]i in both groups of muscle cells. Conclusion: Skeletal muscles of the UP exhibit chronic elevation of [Ca2+]i that can be partially reduced by application of 8-bromo-cADPR. cADPR was able to mobilize Ca2+ from intracellular stores, by a mechanism that is independent of ryanodine or inositol trisphosphate receptors. It can be postulated that an alteration in the cADPR-signaling pathway may exist in skeletal muscle of the patients suffering from uremic myopathy.

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