SKELETAL-MUSCLE SARCOPLASMIC-RETICULUM PHENOTYPE IN MYOTONIC-DYSTROPHY

In this study we investigated the sarcoplasmic reticulum (SR), alongsi de myofibrillar phenotype, in muscle samples from five Myotonic Dystro phy (DM) patients and five control individuals. DM muscles exhibited a s a common feature, a decrease in the slow isoform of myosin heavy cha in (MHC) and of troponin C in myofibrils. We observed a match between myofibrillar changes and changes in SR membrane markers specific to fi ber type, i.e. the fast (SERCA1) Ca2+-ATPase isoform increased concomi tantly with a decrease of protein phospholamban (PLB), which in native SR membranes colocalizes with the slow (SERCA2a) SR Ca2+-ATPase, and regulates its activity depending on phosphorylation by protein kinases . Our results outline a cellular process selectively affecting slow-tw itch fibers, and non-degenerative in nature, since neither the total n umber of Ca2+-pumps or of ryanodine receptor/Ca2+-release channels, or their ratio to the dihydropyridine receptor/voltage sensor in junctio nal transverse tubules, were found to be significantly changed in DM m uscle. The only documented, apparently specific molecular changes asso ciated with this process in the SR of DM muscle, are the defective exp ression of the slow/cardiac isoform of Ca2+-binding protein calsequest rin, together with an increased phosphorylation activity of membrane-b ound 60 kDa Ca2+-calmodulin (CaM) dependent protein kinase. Enhanced p hosphorylation of PLB by membrane-bound Ca2+-CaM protein kinase also a ppeared to be most pronounced in biopsy from a patient with a very hig h CTG expansion, as was the overall 'slow-to-fast' transformation of t he same muscle biopsy. Animal studies showed that endogenous Ca2+-CaM protein kinase exerts a dual activatory role on SERCA2a SR Ca2+-ATPase , i.e. either by direct phosphorylation of the Ca2+-ATPase protein, or mediated by phosphorylation of PLB. Our results seem to be consistent with a maturational-related abnormality and/or with altered modulator y mechanisms of SR Ca2+-transport in DM slow-twitch muscle fibers.