title: Pseudouridine synthase 1 deficient mice, a model for Mitochondrial Myopathy with Sideroblastic Anemia, exhibit muscle morphology and physiology alterations.
abstract: Mitochondrial myopathy with lactic acidosis and sideroblastic anemia (MLASA) is an oxidative phosphorylation disorder, with primary clinical manifestations of myopathic exercise intolerance and a macrocytic sideroblastic anemia. One cause of MLASA is recessive mutations in PUS1, which encodes pseudouridine (Ψ) synthase 1 (Pus1p). Here we describe a mouse model of MLASA due to mutations in PUS1. As expected, certain Ψ modifications were missing in cytoplasmic and mitochondrial tRNAs from Pus1(-/-) animals. Pus1(-/-) mice were born at the expected Mendelian frequency and were non-dysmorphic. At 14 weeks the mutants displayed reduced exercise capacity. Examination of tibialis anterior (TA) muscle morphology and histochemistry demonstrated an increase in the cross sectional area and proportion of myosin heavy chain (MHC) IIB and low succinate dehydrogenase (SDH) expressing myofibers, without a change in the size of MHC IIA positive or high SDH myofibers. Cytochrome c oxidase activity was significantly reduced in extracts from red gastrocnemius muscle from Pus1(-/-) mice. Transmission electron microscopy on red gastrocnemius muscle demonstrated that Pus1(-/-) mice also had lower intermyofibrillar mitochondrial density and smaller mitochondria. Collectively, these results suggest that alterations in muscle metabolism related to mitochondrial content and oxidative capacity may account for the reduced exercise capacity in Pus1(-/-) mice.
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, Public Health Research Center, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Mangum
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, Public Health Research Center, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Hardee
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, Public Health Research Center, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Fix
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, Public Health Research Center, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Puppa
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina, School of Medicine, Columbia, SC 29209, USA.
authors.forename: Johnathon
authors.initials: J
authors.lastname: Elkes
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Altomare
authors.affiliation: Medical Genetics Institute, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Bykhovskaya
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Dean R
authors.initials: DR
authors.lastname: Campagna
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Schmidt
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Anoop K
authors.initials: AK
authors.lastname: Sendamarai
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Hart G W
authors.initials: HG
authors.lastname: Lidov
authors.affiliation: Animal Resource Facility, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Shayne C
authors.initials: SC
authors.lastname: Barlow
authors.affiliation: Medical Genetics Institute, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Fischel-Ghodsian
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, Public Health Research Center, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Carson
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina, School of Medicine, Columbia, SC 29209, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Patton
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006651:Histocytochemistry; D006836:Hydro-Lyases / Q000172:deficiency*; D017241:MELAS Syndrome / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009132:Muscles / Q000473:pathology* / Q000502:physiology*
chemical_list: D006836:Hydro-Lyases; C022479:pseudouridylate synthetase