title: Lipid accumulation in dysferlin-deficient muscles.
abstract: Dysferlin is a membrane associated protein involved in vesicle trafficking and fusion. Defects in dysferlin result in limb-girdle muscular dystrophy type 2B and Miyoshi myopathy in humans and myopathy in A/J(dys-/-) and BLAJ mice, but the pathomechanism of the myopathy is not understood. Oil Red O staining showed many lipid droplets within the psoas and quadriceps muscles of dysferlin-deficient A/J(dys-/-) mice aged 8 and 12 months, and lipid droplets were also conspicuous within human myofibers from patients with dysferlinopathy (but not other myopathies). Electron microscopy of 8-month-old A/J(dys-/-) psoas muscles confirmed lipid droplets within myofibers and showed disturbed architecture of myofibers. In addition, the presence of many adipocytes was confirmed, and a possible role for dysferlin in adipocytes is suggested. Increased expression of mRNA for a gene involved in early lipogenesis, CCAAT/enhancer binding protein-δ, in 3-month-old A/J(dys-/-) quadriceps (before marked histopathology is evident), indicates early induction of lipogenesis/adipogenesis within dysferlin-deficient muscles. Similar results were seen for dysferlin-deficient BLAJ mice. These novel observations of conspicuous intermyofibrillar lipid and progressive adipocyte replacement in dysferlin-deficient muscles present a new focus for investigating the mechanisms that result in the progressive decline of muscle function in dysferlinopathies.
authors.affiliation: Schools of Anatomy, Physiology and Human Biology, University of Western Australia, Perth, Australia. Electronic address: miranda.grounds@uwa.edu.au.
authors.forename: Miranda D
authors.initials: MD
authors.lastname: Grounds
authors.affiliation: Schools of Anatomy, Physiology and Human Biology, University of Western Australia, Perth, Australia.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Terrill
authors.affiliation: Schools of Anatomy, Physiology and Human Biology, University of Western Australia, Perth, Australia; CHIRI Biosciences Research Precinct, School of Biomedical Sciences, Curtin University, Perth, Australia.
authors.forename: Hannah G
authors.initials: HG
authors.lastname: Radley-Crabb
authors.affiliation: Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
authors.forename: Terry
authors.initials: T
authors.lastname: Robertson
authors.affiliation: Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Papadimitriou
authors.affiliation: Muscle Research Unit, Experimental and Clinical Research Center, Berlin, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Spuler
authors.affiliation: Schools of Anatomy, Physiology and Human Biology, University of Western Australia, Perth, Australia.
authors.forename: Tea
authors.initials: T
authors.lastname: Shavlakadze
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000818:Animals; D049310:Distal Myopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000073939:Dysferlin; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C114839:DYSF protein, human; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins