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.

Campistol JM: Uremic myopathy. Kidney Int 2002;62:1901–1913.
Serratrice G, et al: Neuropathies, myopathies and neuromyopathies in chronic uremic patients. Presse Méd 1967;75:1835–1838.
Metra M, et al: Improvement in exercise capacity after correction of anemia in patients with end-stage renal failure. Am J Cardiol 1991;68:1060–1066.
Penpargkul S, Bhan AK, Scheuer J: Studies of subcellular control factors in hearts of uremic rats. J Lab Clin Med 1976;88:563–570.
Wanner C, Schollmeyer P, Horl WH: Serum carnitine levels and carnitine esters of patients after kidney transplantation: Role of immunosuppression. Metabolism 1988;37:263–267.
Savica V, et al: Plasma and muscle carnitine levels in haemodialysis patients with morphological-ultrastructural examination of muscle samples. Nephron 1983;35:232–236.
Lopez JR, et al: Dysfunction of myoplasmic Ca2+ regulation in skeletal muscle from predialytic uremic patients. Nephron 1995;70:270.
Galione A: Cyclic ADP-ribose: A new way to control calcium. Science 1993;259:325–326.
Lee HC, et al: Structural determination of a cyclic metabolite of NAD+ with intracellular Ca2+-mobilizing activity. J Biol Chem 1989;264:1608–1615.
Lee HC, Aarhus R: Wide distribution of an enzyme that catalyzes the hydrolysis of cyclic ADP-ribose. Biochim Biophys Acta 1993;1164:68–74.
Lee HC, Aarhus R: ADP-ribosyl cyclase: An enzyme that cyclizes NAD+ into a calcium-mobilizing metabolite. Cell Regul 1991;2:203–209.
Guo X, Laflamme MA, Becker PL: Cyclic ADP-ribose does not regulate sarcoplasmic reticulum Ca2+ release in intact cardiac myocytes. Circ Res 1996;79:147–151.
Prakash YS, et al: cADP ribose and [Ca2+]i regulation in rat cardiac myocytes. Am J Physiol 2000;279:H1482–H1489.
Meszaros LG, Bak J, Chu A: Cyclic ADP-ribose as an endogenous regulator of the non-skeletal type ryanodine receptor Ca2+ channel. Nature 1993;364:76–79.
Morrissette J, et al: Cyclic ADP-ribose induced Ca2+ release in rabbit skeletal muscle sarcoplasmic reticulum. FEBS Lett 1993;330:270–274.
Lopez JR, et al: Cyclic ADP-ribose induces a larger than normal calcium release in malignant hyperthermia-susceptible skeletal muscle fibers. Pflügers Arch 2000;440:236–242.
Fruen BR, Mickelson JR, Louis CF: Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors. J Biol Chem 1997;272:26965–26971.
Lahouratate P, Guibert J, Faivre JF: cADP-ribose releases Ca2+ from cardiac sarcoplasmic reticulum independently of ryanodine receptor. Am J Physiol 1997;273:H1082–H1089.
Copello JA, Jeyakumar LH, Ogunbunmi E, Fleischer S: Lack of effect of cADP-ribose and NAADP on the activity of skeletal muscle and heart ryanodine receptors. Cell Calcium 2001;30:269–284.
Lopez JR, Parra L: Inositol 1,4,5-trisphosphate increases myoplasmic [Ca2+] in isolated muscle fibers. Depolarization enhances its effects. Cell Calcium 1991;12:543–557.
Lopez JR, et al: Determination of ionic calcium in frog skeletal muscle fibers. Biophys J 1983;43:1–4.
Lopez JR, et al: Direct measurement of intracellular free magnesium in frog skeletal muscle using magnesium-selective microelectrodes. Biochim Biophys Acta 1984;804:1–7.
Lopez JR, Terzic A: Inositol 1,4,5-trisphosphate-induced Ca2+ release is regulated by cytosolic Ca2+ in intact skeletal muscle. Pflügers Arch 1996;432:782–790.
Grundfest H, Kao CY, Altamirano M: Bioelectric effects of ions microinjected into the giant axon of Loligo. J Gen Physiol 1954;38:245–282.
Da Silva CP, et al: Quantification of intracellular levels of cyclic ADP-ribose by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1998;707:43–50.
Rios E, Pizarro G: Voltage sensor of excitation-contraction coupling in skeletal muscle. Physiol Rev 1991;71:849–908.
Meissner G: Ryanodine activation and inhibition of the Ca2+ release channel of sarcoplasmic reticulum. J Biol Chem 1986;261:6300–6306.
Rousseau E, Smith JS, Meissner G: Ryanodine modifies conductance and gating behavior of single Ca2+ release channel. Am J Physiol 1987;253:C364–C368.
Berridge MJ: Elementary and global aspects of calcium signalling. J Physiol 1997;499:291–306.
Iino S, et al: Actions of cADP-ribose and its antagonists on contraction in guinea pig isolated ventricular myocytes. Influence of temperature. Circ Res 1997;81:879–884.
Lopez JR, et al: Myoplasmic free [Ca2+] during a malignant hyperthermia episode in swine. Muscle Nerve 1988;11:82–88.
Carafoli E, Brini M: Calcium pumps: Structural basis for and mechanism of calcium transmembrane transport. Curr Opin Chem Biol 2000;4:152–161.
Lopez JR, Lopez MJ, Sanchez V: Dysfunction in myoplasmic Ca2+ homeostasis in neuroleptic malignant syndrome. Acta Cient Venez 1989;40:232–234.
Lopez JR, et al: Elevated myoplasmic calcium in exercise-induced equine rhabdomyolysis. Pflügers Arch 1995;430:293–295.
Lopez JR, et al: Myoplasmic Ca2+ concentration during exertional rhabdomyolysis. Lancet 1995;345:424–425.
Lopez JR, et al: Myoplasmic (Ca2+) in Duchenne muscular dystrophy patients. Acta Cient Venez 1987;38:503–504.
Sitsapesan R, Williams AJ: Cyclic ADP-ribose and related compounds activate sheep skeletal sarcoplasmic reticulum Ca2+ release channel. Am J Physiol 1995;268:C1235–C1240.
Kim H, Jacobson EL, Jacobson MK: Synthesis and degradation of cyclic ADP-ribose by NAD glycohydrolases. Science 1993;261:1330–1333.
Galione A, Lee HC, Busa WB: Ca2+-induced Ca2+ release in sea urchin egg homogenates: Modulation by cyclic ADP-ribose. Science 1991;253:1143–1146.
Kannan MS, et al: Cyclic ADP-ribose stimulates sarcoplasmic reticulum calcium release in porcine coronary artery smooth muscle. Am J Physiol 1996;270:H801–H806.
Walseth TF, et al: Identification of cyclic ADP-ribose-binding proteins by photoaffinity labeling. J Biol Chem 1993;268:26686–26691.
Noguchi N, et al: Cyclic ADP-ribose binds to FK506-binding protein 12.6 to release Ca2+ from islet microsomes. J Biol Chem 1997;272:3133–3136.
Bastide B, Snoeckx K, Mounier Y: ADP-ribose stimulates the calcium release channel RyR1 in skeletal muscle of rat. Biochem Biophys Res Commun 2002;296:1267–1271.
Guse AH, et al: Ca2+ entry induced by cyclic ADP-ribose in intact T-lymphocytes. J Biol Chem 1997;272:8546–8550.
Walseth TF, Lee HC: Synthesis and characterization of antagonists of cyclic-ADP-ribose-induced Ca2+ release. Biochim Biophys Acta 1993;1178:235–242.
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