source: Brain : a journal of neurology

year: 2021

authors: Habets LE,Bartels B,Asselman FL,Hooijmans MT,van den Berg S,Nederveen AJ,van der Pol WL,Jeneson JAL

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 etiology.

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 31phosphorus magnetic resonance spectroscopy, the modality of choice to interrogate muscle energetics and phenotypic fiber 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. 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 vivo 31phosphorus magnetic resonance spectroscopy identified white-to-red remodeling of residual proximal arm musculature in patients on basis of altered intramuscular inorganic phosphate accumulation during arm-cycling in red versus white and intermediate myofibers. 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 myofibers in patients demonstrating mitochondrial ATP synthetic dysfunction in this particular fiber type.

This study provides 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 myofibers that contract fastest and strongest. Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibers provides both a possible clue to understanding the apparent vulnerability of this particular fiber type in 5q spinal muscular atrophy type 3 and 4 as well as a new biomarker and target for therapy.

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