Sarcoplasmic Reticulum Calcium Handling in Maturing Skeletal Muscle From Two Models of Dystrophic Mice

dc.contributor.authorRittler, Matthew Roberten
dc.contributor.committeechairGrange, Robert W.en
dc.contributor.committeememberWilliams, Jay H.en
dc.contributor.committeememberDuncan, Robert B. Jr.en
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.date.accessioned2014-03-14T20:47:34Zen
dc.date.adate2002-12-03en
dc.date.available2014-03-14T20:47:34Zen
dc.date.issued2002-10-23en
dc.date.rdate2003-12-03en
dc.date.sdate2002-11-07en
dc.description.abstractDuchenne's muscular dystrophy (DMD) is a debilitating disease that affects approximately 1 in 3500 boys, with many DMD patients dying before the age of 20 due to cardio-respiratory complications. DMD is the result of defects in the gene that encodes dystrophin, an integral muscle membrane protein. Although the genetic defect has been identified, the relation between the absence of expressed dystrophin and the mechanisms leading to its onset are still unclear. One possibility is that disrupted calcium (Ca²⁺) handling by the sarcoplasmic reticulum (SR) leads to an increased cytosolic Ca²⁺ concentration that activates proteolytic and apoptotic pathways that initiate muscle fiber death. However, little is known about the role of disrupted SR function in the onset of DMD. The purpose of this study was to test the hypothesis that altered calcium cycling by the SR could contribute to elevated cytosolic Ca²⁺ levels in the early stages of DMD, and thereby account for the onset of disease pathogenesis. Rates of SR Ca²⁺ uptake and release were determined in quadriceps muscles obtained from maturing dystrophic and control mice prior to the overt signs of the disease at ages ~9 and 21 days. In addition, the content of several key Ca²⁺ handling proteins, including two isoforms of the sarco(endo)plasmic reticulum ATPase pump (SERCA 1 & 2), ryanodine receptor type 1 (RyR1), parvalbumin, and calsequestrin were determined by Western analysis. Two dystrophic mouse models were used, the mdx mouse which lacks dystrophin, and the mdx:utrophin-deficient (mdx:utrn<sup>-/-</sup>) mouse which also lacks utrophin, a protein homolog of dystrophin. The rate of SR Ca²⁺ uptake in quadriceps muscles of mdx/utrn<sup>-/-</sup> mice aged 21 days was 73.1% and 61.3% higher than age-matched control and mdx muscles, respectively (p < 0.05). There was no difference in SR Ca²⁺ release rates between the genotypes at either age. There were significant increases in the content of each of the calcium handling proteins with age (p < 0.05), but no significant differences were detected between genotypes at either age. These data demonstrate the Ca²⁺ release rates of dystrophic SR are not compromised, but suggest the increased uptake rates of mdx:utrn<sup>-/-</sup> SR may be an adaptation to increased cytosolic calcium levels, and/or be due to changes in intrinsic SERCA function and/or regulation. The role of increased SR Ca²⁺ uptakes rates in onset of DMD pathogenesis can not be directly determined from the present data; therefore it is suggested that future studies directly assess cytosolic Ca²⁺ concentration and examine the role of SERCA regulatory proteins in intact fibers obtained from mdx:utrn<sup>-/-</sup> muscles at age 21 days.en
dc.description.degreeMaster of Scienceen
dc.identifier.otheretd-11072002-115048en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-11072002-115048/en
dc.identifier.urihttp://hdl.handle.net/10919/35619en
dc.publisherVirginia Techen
dc.relation.haspartThesis.PDFen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectParvalbuminen
dc.subjectRyanodineen
dc.subjectDuchenneen
dc.subjectCalsequestrinen
dc.subjectSERCAen
dc.titleSarcoplasmic Reticulum Calcium Handling in Maturing Skeletal Muscle From Two Models of Dystrophic Miceen
dc.typeThesisen
thesis.degree.disciplineHuman Nutrition, Foods, and Exerciseen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen

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