Pseudouridine synthase 1 deficient mice, a model for Mitochondrial Myopathy with Sideroblastic Anemia, exhibit muscle morphology and physiology alterations

Joshua E. Mangum, Justin P. Hardee, Dennis K. Fix, Melissa J. Puppa, Johnathon Elkes, Diego Altomare, Yelena Bykhovskaya, Dean R. Campagna, Paul J. Schmidt, Anoop K. Sendamarai, Hart G.W. Lidov, Shayne C. Barlow, Nathan Fischel-Ghodsian, Mark D. Fleming, James Carson, Jeffrey R. Patton

Research output: Contribution to journalArticle

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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 synthase 1 (Pus1p). Here we describe a mouse model of MLASA due to mutations in PUS1. As expected, certain modifications were missing in cytoplasmic and mitochondrial tRNAs from Pus1 â'/â' animals. Pus1 â'/â' 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 â'/â' mice. Transmission electron microscopy on red gastrocnemius muscle demonstrated that Pus1 â'/â' 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 â'/â' mice.

Original languageEnglish (US)
Article number26202
JournalScientific Reports
Volume6
DOIs
StatePublished - May 20 2016

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Muscles
Succinate Dehydrogenase
Myosin Heavy Chains
Skeletal Muscle
Sideroblastic Anemia
Macrocytic Anemia
Mutation
Oxidative Phosphorylation
Electron Transport Complex IV
Transfer RNA
Transmission Electron Microscopy
Mitochondria
Myopathy with lactic acidosis and sideroblastic anemia
pseudouridylate synthetase

All Science Journal Classification (ASJC) codes

  • General

Cite this

Pseudouridine synthase 1 deficient mice, a model for Mitochondrial Myopathy with Sideroblastic Anemia, exhibit muscle morphology and physiology alterations. / Mangum, Joshua E.; Hardee, Justin P.; Fix, Dennis K.; Puppa, Melissa J.; Elkes, Johnathon; Altomare, Diego; Bykhovskaya, Yelena; Campagna, Dean R.; Schmidt, Paul J.; Sendamarai, Anoop K.; Lidov, Hart G.W.; Barlow, Shayne C.; Fischel-Ghodsian, Nathan; Fleming, Mark D.; Carson, James; Patton, Jeffrey R.

In: Scientific Reports, Vol. 6, 26202, 20.05.2016.

Research output: Contribution to journalArticle

Mangum, JE, Hardee, JP, Fix, DK, Puppa, MJ, Elkes, J, Altomare, D, Bykhovskaya, Y, Campagna, DR, Schmidt, PJ, Sendamarai, AK, Lidov, HGW, Barlow, SC, Fischel-Ghodsian, N, Fleming, MD, Carson, J & Patton, JR 2016, 'Pseudouridine synthase 1 deficient mice, a model for Mitochondrial Myopathy with Sideroblastic Anemia, exhibit muscle morphology and physiology alterations', Scientific Reports, vol. 6, 26202. https://doi.org/10.1038/srep26202
Mangum, Joshua E. ; Hardee, Justin P. ; Fix, Dennis K. ; Puppa, Melissa J. ; Elkes, Johnathon ; Altomare, Diego ; Bykhovskaya, Yelena ; Campagna, Dean R. ; Schmidt, Paul J. ; Sendamarai, Anoop K. ; Lidov, Hart G.W. ; Barlow, Shayne C. ; Fischel-Ghodsian, Nathan ; Fleming, Mark D. ; Carson, James ; Patton, Jeffrey R. / Pseudouridine synthase 1 deficient mice, a model for Mitochondrial Myopathy with Sideroblastic Anemia, exhibit muscle morphology and physiology alterations. In: Scientific Reports. 2016 ; Vol. 6.
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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 synthase 1 (Pus1p). Here we describe a mouse model of MLASA due to mutations in PUS1. As expected, certain modifications were missing in cytoplasmic and mitochondrial tRNAs from Pus1 {\^a}'/{\^a}' animals. Pus1 {\^a}'/{\^a}' 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 {\^a}'/{\^a}' mice. Transmission electron microscopy on red gastrocnemius muscle demonstrated that Pus1 {\^a}'/{\^a}' 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 {\^a}'/{\^a}' mice.",
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AU - Puppa, Melissa J.

AU - Elkes, Johnathon

AU - Altomare, Diego

AU - Bykhovskaya, Yelena

AU - Campagna, Dean R.

AU - Schmidt, Paul J.

AU - Sendamarai, Anoop K.

AU - Lidov, Hart G.W.

AU - Barlow, Shayne C.

AU - Fischel-Ghodsian, Nathan

AU - Fleming, Mark D.

AU - Carson, James

AU - Patton, Jeffrey R.

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