Multimodal MRI and 31P-MRS Investigations of the ACTA1(Asp286Gly) Mouse Model of Nemaline Myopathy Provide Evidence of Impaired In Vivo Muscle Function, Altered Muscle Structure and Disturbed Energy Metabolism

Abstract

Nemaline myopathy (NM), the most common non-dystrophic congenital disease of skeletal muscle, can be caused by mutations in the skeletal muscle α-actin gene (ACTA1) (~25% of all NM cases and up to 50% of severe forms of NM). Muscle function of the recently generated transgenic mouse model carrying the human Asp286Gly mutation in the ACTA1 gene (Tg(ACTA1)Asp286Gly) has been mainly investigated in vitro. Therefore, we aimed at providing a comprehensive picture of the in vivo hindlimb muscle function of Tg(ACTA1)Asp286Gly mice by combining strictly noninvasive investigations. Skeletal muscle anatomy (hindlimb muscles, intramuscular fat volumes) and microstructure were studied using multimodal magnetic resonance imaging (Dixon, T2, Diffusion Tensor Imaging [DTI]). Energy metabolism was studied using 31-phosphorus Magnetic Resonance Spectroscopy (31P-MRS). Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (1–150 Hz) and a fatigue protocol (6 min–1.7 Hz). Tg(ACTA1)Asp286Gly mice showed a mild muscle weakness as illustrated by the reduction of both absolute (30%) and specific (15%) maximal force production. Dixon MRI did not show discernable fatty infiltration in Tg(ACTA1)Asp286Gly mice indicating that this mouse model does not reproduce human MRI findings. Increased T2 values were observed in Tg(ACTA1)Asp286Gly mice and might reflect the occurrence of muscle degeneration/regeneration process. Interestingly, T2 values were linearly related to muscle weakness. DTI experiments indicated lower λ2 and λ3 values in Tg(ACTA1)Asp286Gly mice, which might be associated to muscle atrophy and/or the presence of histological anomalies. Finally 31P-MRS investigations illustrated an increased anaerobic energy cost of contraction in Tg(ACTA1)Asp286Gly mice, which might be ascribed to contractile and non-contractile processes. Overall, we provide a unique set of information about the anatomic, metabolic and functional consequences of the Asp286Gly mutation that might be considered as relevant biomarkers for monitoring the severity and/or the progression of NM and for assessing the efficacy of potential therapeutic interventions.

In vivo characterization of skeletal muscle function in nebulin‐deficient mice

“…Despite the Sol muscle hypertrophy, the total hindlimb muscles volume was severely reduced in Neb ‐cKO mice (−45%) in comparison with WT mice. Muscle wasting in Neb ‐cKO mice is higher than the 20% and 15% reduction of hindlimb muscles volume we previously observed in the KI Acta1 H40Y and Tg ACTA1 D286G mouse models, which reproduce severe and mild features of NEM patients, respectively. Thus, the Neb ‐cKO model displayed muscle wasting that is similar to the younger mice but more severe than the one reported in the two other NEM mouse models.…”

Relationships between tissue microstructure and the diffusion tensor in simulated skeletal muscle

“…The use of short diffusion times with short TEs in the diffusion literature is not unique to this study, but is reported across the literature in studies using a spin‐echo DTI pulse sequence. Although the diffusion time used in this study was short (9 ms), short diffusion times have been used in studies using high‐field strength (6.3T+) MRI with comparable TE (Δ/TE; 10 ms/25 ms in Zhang et al , 10 ms/20 ms in Gineste et al , 11.7 ms/29 ms in Ababneh et al , 12 ms/21 ms in Fan et al , 13 ms/30 ms in Heemskerk et al , and 13 ms/30 ms in Heemskerk et al ). In these studies, because T 2 relaxation decreases with increasing magnetic field strength, the time between diffusion gradients was shortened to minimize TE, to maximize SNR.…”

Skeletal muscle quantitative nuclear magnetic resonance imaging and spectroscopy as an outcome measure for clinical trials (part II)

“…структурных миопатиях, по крайней мере на моделях животных с генетическими мутациями небулина, AC-TA1 или динамина [39][40][41][42]. Это говорит о том, что определенная степень клеточной дезорганизации может достаточно повлиять на внутриклеточную мо-бильность, чтобы изменить сигнал Т2.…”