Abstract
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.
Highlights
Considered a rare disease, nemaline myopathy (NM) is the most common of the non-dystrophic congenital myopathies and is characterized by muscle weakness and the presence of rod shaped structures in the muscle fibers [1]
Mutations in seven genes have been identified so far as causing NM: actin alpha 1 (ACTA1), alpha-tropomyosin-3 and beta-tropomyosin (TPM3 and TPM2), nebulin (NEB), troponin T type 1 (TNNT1), cofilin-2 (CFL2), and kelch repeat and BTB (POZ) domain containing 13 (KBTBD13) genes. The majority of these genes encode proteins associated with the thin filament of the sarcomere so that NM is considered as a thin filament myopathy [4,5]
Mechanical Performance As illustrated in figure 2A, a 40% reduction (P,0.05) in absolute maximal tetanic force was quantified in H40Y mice as compared to wildtype female littermates (WT) mice
Summary
Considered a rare disease, nemaline myopathy (NM) is the most common of the non-dystrophic congenital myopathies and is characterized by muscle weakness and the presence of rod shaped structures in the muscle fibers [1]. Mutations in seven genes have been identified so far as causing NM: actin alpha 1 (ACTA1), alpha-tropomyosin-3 and beta-tropomyosin (TPM3 and TPM2), nebulin (NEB), troponin T type 1 (TNNT1), cofilin-2 (CFL2), and kelch repeat and BTB (POZ) domain containing 13 (KBTBD13) genes. The majority of these genes encode proteins associated with the thin filament of the sarcomere so that NM is considered as a thin filament myopathy [4,5]. NM related to ACTA1 mutations represents 15% to 25% of NM cases and up to 50% of the most severely affected patients [6,7]. Mild and even adult-onset disease has been observed in a few patients [11,12]
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