Combined MRI and 31P-MRS Investigations of the ACTA1H40Y Mouse Model of Nemaline Myopathy Show Impaired Muscle Function and Altered Energy MetabolismReport as inadecuate




Combined MRI and 31P-MRS Investigations of the ACTA1H40Y Mouse Model of Nemaline Myopathy Show Impaired Muscle Function and Altered Energy Metabolism - Download this document for free, or read online. Document in PDF available to download.

Nemaline myopathy NM is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. Mutations in the skeletal muscle α-actin gene ACTA1 account for ∼25% of all NM cases and are the most frequent cause of severe forms of NM. So far, the mechanisms underlying muscle weakness in NM patients remain unclear. Additionally, recent Magnetic Resonance Imaging MRI studies reported a progressive fatty infiltration of skeletal muscle with a specific muscle involvement in patients with ACTA1 mutations. We investigated strictly noninvasively the gastrocnemius muscle function of a mouse model carrying a mutation in the ACTA1 gene H40Y. Skeletal muscle anatomy hindlimb muscles and fat volumes and energy metabolism were studied using MRI and 31Phosphorus magnetic resonance spectroscopy. Skeletal muscle contractile performance was investigated while applying a force-frequency protocol from 1–150 Hz and a fatigue protocol 80 stimuli at 40 Hz. H40Y mice showed a reduction of both absolute −40% and specific −25% maximal force production as compared to controls. Interestingly, muscle weakness was associated with an improved resistance to fatigue +40% and an increased energy cost. On the contrary, the force frequency relationship was not modified in H40Y mice and the extent of fatty infiltration was minor and not different from the WT group. We concluded that the H40Y mouse model does not reproduce human MRI findings but shows a severe muscle weakness which might be related to an alteration of intrinsic muscular properties. The increased energy cost in H40Y mice might be related to either an impaired mitochondrial function or an alteration at the cross-bridges level. Overall, we provided a unique set of anatomic, metabolic and functional biomarkers that might be relevant for monitoring the progression of NM disease but also for assessing the efficacy of potential therapeutic interventions at a preclinical level.



Author: Charlotte Gineste, Yann Le Fur, Christophe Vilmen, Arnaud Le Troter, Emilie Pecchi, Patrick J. Cozzone, Edna C. Hardeman, David B

Source: http://plos.srce.hr/



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