title: A mutation in alpha-tropomyosin(slow) affects muscle strength, maturation and hypertrophy in a mouse model for nemaline myopathy.
abstract: Nemaline myopathy is a hereditary disease of skeletal muscle defined by a distinct pathology of electron-dense accumulations within the sarcomeric units called rods, muscle weakness and, in most cases, a slow oxidative (type 1) fiber predominance. We generated a transgenic mouse model to study this disorder by expressing an autosomal dominant mutant of alpha-tropomyosin(slow) previously identified in a human cohort. Rods were found in all muscles, but to varying extents which did not correlate with the amount of mutant protein present. In addition, a pathological feature not commonly associated with this disorder, cytoplasmic bodies, was found in the mouse and subsequently identified in human samples. Muscle weakness is a major feature of this disease and was examined with respect to fiber composition, degree of rod-containing fibers, fiber mechanics and fiber diameter. Hypertrophy of fast, glycolytic (type 2B) fibers was apparent at 2 months of age. Muscle weakness was apparent in mice at 5-6 months of age, mimicking the late onset observed in humans with this mutation. The late onset did not correlate with observed changes in fiber type and rod pathology. Rather, the onset of muscle weakness correlates with an age-related decrease in fiber diameter and suggests that early onset is prevented by hypertrophy of fast, glycolytic fibers. We suggest that the clinical phenotype is precipitated by a failure of the hypertrophy to persist and therefore compensate for muscle weakness.
authors.affiliation: Muscle Development Unit, Children's Medical Research Institute, Locked Bag 23, Wentworthville, New South Wales 2145, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Corbett
authors.forename: C S
authors.initials: CS
authors.lastname: Robinson
authors.forename: G F
authors.initials: GF
authors.lastname: Dunglison
authors.forename: N
authors.initials: N
authors.lastname: Yang
authors.forename: J E
authors.initials: JE
authors.lastname: Joya
authors.forename: A W
authors.initials: AW
authors.lastname: Stewart
authors.forename: C
authors.initials: C
authors.lastname: Schnell
authors.forename: P W
authors.initials: PW
authors.lastname: Gunning
authors.forename: K N
authors.initials: KN
authors.lastname: North
authors.forename: E C
authors.initials: EC
authors.lastname: Hardeman
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001120:Arginine / Q000235:genetics; D004195:Disease Models, Animal; D004210:Dissection; D005260:Female; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D006984:Hypertrophy; D002479:Inclusion Bodies / Q000473:pathology / Q000648:ultrastructure; D008715:Methionine / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008870:Microtubules / Q000473:pathology / Q000648:ultrastructure; D024510:Muscle Development; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D018908:Muscle Weakness / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D017696:Myopathies, Nemaline / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010084:Oxidation-Reduction; D017354:Point Mutation; D012333:RNA, Messenger / Q000096:biosynthesis; D012519:Sarcoplasmic Reticulum / Q000473:pathology / Q000648:ultrastructure; D013324:Strontium / Q000494:pharmacology; D014335:Tropomyosin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D014335:Tropomyosin; D001120:Arginine; D008715:Methionine; C025700:strontium chloride; D013324:Strontium