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Neuromuscul Disord. 1996 Jan;6(1):33-47.

Skeletal muscle sarcoplasmic reticulum phenotype in myotonic dystrophy.

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Department of Biomedical Sciences, University of Padova, Italy.


In this study we investigated the sarcoplasmic reticulum (SR), alongside myofibrillar phenotype, in muscle samples from five Myotonic Dystrophy (DM) patients and five control individuals. DM muscles exhibited as a common feature, a decrease in the slow isoform of myosin heavy chain (MHC) and of troponin C in myofibrils. We observed a match between myofibrillar changes and changes in SR membrane markers specific to fiber type, i.e. the fast (SERCA1) Ca(2+)-ATPase isoform increased concomitantly with a decrease of protein phospholamban (PLB), which in native SR membranes colocalizes with the slow (SERCA2a) SR Ca(2+)-ATPase, and regulates its activity depending on phosphorylation by protein kinases. Our results outline a cellular process selectively affecting slow-twitch fibers, and non-degenerative in nature, since neither the total number of Ca(2+)-pumps or of ryanodine receptor/Ca(2+)-release channels, or their ratio to the dihydropyridine receptor/voltage sensor in junctional transverse tubules, were found to be significantly changed in DM muscle. The only documented, apparently specific molecular changes associated with this process in the SR of DM muscle, are the defective expression of the slow/cardiac isoform of Ca(2+)-binding protein calsequestrin, together with an increased phosphorylation activity of membrane-bound 60 kDa Ca(2+)-calmodulin (CaM) dependent protein kinase. Enhanced phosphorylation of PLB by membrane-bound Ca(2+)-CaM protein kinase also appeared to be most pronounced in biopsy from a patient with a very high CTG expansion, as was the overall 'slow-to-fast' transformation of the same muscle biopsy. Animal studies showed that endogenous Ca(2+)-CaM protein kinase exerts a dual activatory role on SERCA2a SR Ca(2+)-ATPase, i.e. either by direct phosphorylation of the Ca(2+)-ATPase protein, or mediated by phosphorylation of PLB. Our results seem to be consistent with a maturational-related abnormality and/or with altered modulatory mechanisms of SR Ca(2+)-transport in DM slow-twitch muscle fibers.

[Indexed for MEDLINE]

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