Altered Ca2+ homeostasis in human uremic skeletal muscle: possible involvement of cADPR in elevation of intracellular resting [Ca2+].
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 beta-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 measured using 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.


CONCLUSIONS
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.
López
José R
JR
Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela. lopez@zeus.bwh.harvard.edu
Mijares
Alfredo
A
Rojas
Bianca
B
Linares
Nancy
N
Allen
Paul D
PD
Shtifman
Alexander
A
D000328:Adult; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006706:Homeostasis; D006801:Humans; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009135:Muscular Diseases / Q000209:etiology / Q000378:metabolism*; D014511:Uremia / Q000150:complications / Q000378:metabolism*
D036563:Cyclic ADP-Ribose; D002118:Calcium