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Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy.
Habets, Laura E; Bartels, Bart; Asselman, Fay-Lynn; Hooijmans, Melissa T; van den Berg, Sandra; Nederveen, Aart J; van der Pol, W Ludo; Jeneson, Jeroen A L.
Afiliación
  • Habets LE; Centre for Child Development, Exercise and Physical Literacy, Wilhelmina Children's Hospital, University Medical Centre Utrecht, P.O. Box 85090, 3508 AB Utrecht, the Netherlands.
  • Bartels B; Centre for Child Development, Exercise and Physical Literacy, Wilhelmina Children's Hospital, University Medical Centre Utrecht, P.O. Box 85090, 3508 AB Utrecht, the Netherlands.
  • Asselman FL; UMC Utrecht Brain Centre, Department of Neurology and Neurosurgery, University Medical Centre Utrecht Brain Center, Utrecht University, P.O. Box 85500, 3508 GA Utrecht, the Netherlands.
  • Hooijmans MT; Department of Radiology & Nuclear Medicine, Amsterdam Movement Sciences, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, the Netherlands.
  • van den Berg S; Department of Radiology & Nuclear Medicine, Amsterdam Movement Sciences, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, the Netherlands.
  • Nederveen AJ; Department of Radiology & Nuclear Medicine, Amsterdam Movement Sciences, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, the Netherlands.
  • van der Pol WL; UMC Utrecht Brain Centre, Department of Neurology and Neurosurgery, University Medical Centre Utrecht Brain Center, Utrecht University, P.O. Box 85500, 3508 GA Utrecht, the Netherlands.
  • Jeneson JAL; Centre for Child Development, Exercise and Physical Literacy, Wilhelmina Children's Hospital, University Medical Centre Utrecht, P.O. Box 85090, 3508 AB Utrecht, the Netherlands.
Brain ; 145(4): 1422-1435, 2022 05 24.
Article en En | MEDLINE | ID: mdl-34788410
ABSTRACT
Genetic therapy has changed the prognosis of hereditary proximal spinal muscular atrophy, although treatment efficacy has been variable. There is a clear need for deeper understanding of underlying causes of muscle weakness and exercise intolerance in patients with this disease to further optimize treatment strategies. Animal models suggest that in addition to motor neuron and associated musculature degeneration, intrinsic abnormalities of muscle itself including mitochondrial dysfunction contribute to the disease aetiology. To test this hypothesis in patients, we conducted the first in vivo clinical investigation of muscle bioenergetics. We recruited 15 patients and 15 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. MRI and 31P magnetic resonance spectroscopy, the modality of choice to interrogate muscle energetics and phenotypic fibre-type makeup, was performed of the proximal arm musculature in combination with fatiguing arm-cycling exercise and blood lactate testing. We derived bioenergetic parameter estimates including blood lactate, intramuscular pH and inorganic phosphate accumulation during exercise, and muscle dynamic recovery constants. A linear correlation was used to test for associations between muscle morphological and bioenergetic parameters and clinico-functional measures of muscle weakness. MRI showed significant atrophy of triceps but not biceps muscles in patients. Maximal voluntary contraction force normalized to muscle cross-sectional area for both arm muscles was 1.4-fold lower in patients than in controls, indicating altered intrinsic muscle properties other than atrophy contributed to muscle weakness in this cohort. In vivo31P magnetic resonance spectroscopy identified white-to-red remodelling of residual proximal arm musculature in patients on the basis of altered intramuscular inorganic phosphate accumulation during arm-cycling in red versus white and intermediate myofibres. Blood lactate rise during arm-cycling was blunted in patients and correlated with muscle weakness and phenotypic muscle makeup. Post-exercise metabolic recovery was slower in residual intramuscular white myofibres in patients demonstrating mitochondrial ATP synthetic dysfunction in this particular fibre type. This study provides the first in vivo evidence in patients that degeneration of motor neurons and associated musculature causing atrophy and muscle weakness in 5q spinal muscular atrophy type 3 and 4 is aggravated by disproportionate depletion of myofibres that contract fastest and strongest. Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibres provides both a possible clue to understanding the apparent vulnerability of this particular fibre type in 5q spinal muscular atrophy types 3 and 4 as well as a new biomarker and target for therapy.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Atrofia Muscular Espinal / Debilidad Muscular Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Brain Año: 2022 Tipo del documento: Article País de afiliación: Países Bajos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Atrofia Muscular Espinal / Debilidad Muscular Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Brain Año: 2022 Tipo del documento: Article País de afiliación: Países Bajos