title: Apoptosis-related changes in skeletal muscles of patients with mitochondrial diseases.
abstract: Much interest has recently been shown in apoptosis-mediated roles in the pathophysiology of mitochondrial diseases, because mitochondrial defects are implicated in a wide variety of degenerative diseases. We investigated whether apoptotic events occurred in skeletal muscles of patients with mitochondrial diseases, including chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayer syndrome (KSS), and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). In a immunohistochemical study, stainings for 8-hydroxy-deoxyguanosine (8-OH-dG), 4-hydroxy-nonenal (4-HNE), Mn-SOD, Bcl-2, cytochrome c, DNase I and Bcl-x L showed a pronounced granular distribution in the cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs). On the other hand, the signals for Bax, p53, Fas and caspase 3 were not obviously increased in RRFs. In situ labeling of DNA breaks demonstrated preferential signals not only in myonuclei but also in subsarcolemmal regions of RRFs, indicating that mitochondrial as well as myonuclear DNA is fragmented in RRFs. An immunoblotting study demonstrated that cytochrome c was increased in the cytosol of diseased muscles and that DNase I was increased in mitochondria, compared to that of normal muscles. No difference was observed between protein bands at 20 kDa corresponding to caspase 3 in diseased and normal muscles. These findings demonstrate that these mitochondrial diseases harbor unique apoptosis-related changes that differ from caspase 3-dependent apoptosis. It is thought that these changes are induced by superoxide overproduction and cytochrome c release resulting from an inherent mitochondrial defect and that the events are associated with DNase I activation.
authors.affiliation: First Department of Internal Medicine, School of Medicine, The University of Tokushima, Kuramoto-3, Tokushima 770-8503, Japan. tmitsui@clin.med.tokushima-u.ac.jp
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Umaki
authors.forename: Takao
authors.initials: T
authors.lastname: Mitsui
authors.forename: Itsuro
authors.initials: I
authors.lastname: Endo
authors.forename: Masashi
authors.initials: M
authors.lastname: Akaike
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D007625:Kearns-Sayre Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017241:MELAS Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000473:pathology* / Q000503:physiopathology*; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics / Q000473:pathology / Q000503:physiopathology