Magnetic resonance imaging of mouse skeletal muscle to measure denervation atrophy

Abstract

We assessed the potential of different MRI measures to detect and quantify skeletal muscle changes with denervation in two mouse models of denervation/neurogenic atrophy. Acute complete denervation and chronic partial denervation were examined in calf muscles after sciatic nerve axotomy and in transgenic SOD1 G93A mice, respectively. Serial T 2 , diffusion tensor, and high resolution anatomical images were acquired, and compared to behavioral, histological, and electrophysiological data. Increase in muscle T 2 signal was first detected after sciatic nerve axotomy. Progressive muscle atrophy could be monitored with MRI-based volume measurements, which correlated strongly with postmortem muscle mass measurements. Significant increase in muscle fractional anisotropy and decreases in secondary and tertiary eigenvalues obtained from diffusion tensor imaging (DTI) were observed after denervation. In SOD1 G93A animals, muscle denervation was detected by elevated muscle T 2 and atrophy in the medial gastrocnemius at 10 weeks. Changes in T 2 and muscle volume were first observed in medial gastrocnemius and later in other calf muscles. Alterations in secondary and tertiary eigenvalues obtained from DTI were first observed in tibialis anterior and medial gastrocnemius muscles at age 12 weeks. We propose that MRI of skeletal muscle is a sensitive surrogate outcome measure of denervation atrophy in animal models of neuromuscular disorders, with potential applicability in preclinical therapeutic screening studies in rodents. KeywordsMRI; denervation; muscle atrophy; muscle size; nerve injury; SOD1 Neurogenic muscle atrophy is a common accompaniment of neuromuscular disorders affecting motor neurons, motor spinal roots, and peripheral nerves. Muscle size and/or function are frequently used to monitor neuromuscular diseases clinically as well as in disease models. Transgenic mice are often used as preclinical models of neuromuscular disorders. With the availability of various therapeutic interventions that are ready for preclinical evaluation of neuromuscular disorders, including motor neuron disease and neuropathies, there is increasing *Correspondence to: Jiangyang Zhang, Ph.D, Address: Department of Radiology, Johns Hopkins University School of Medicine, 217 Traylor Bldg, 720 Rutland Ave., Baltimore, MD, 21205, USA, Email: jzhang3@jhmi.edu, Kazim A. Sheikh, MD, Address: Department of Neurology, Johns Hopkins University School of Medicine, 600 N-Wolfe street/509 Pathology Bldg., Baltimore, MD 21205, USA, Tel: 410-614-1196, Fax: 410-502-5459, Email: ksheik@jhmi.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimer...

A 3D Tissue-Printing Approach for Validation of Diffusion Tensor Imaging in Skeletal Muscle

“…7,17,41 Our results demonstrate that as fiber size decreased, an increase in the FA and a decrease in MD were measurable, which is consistent with in vivo findings. 13 Similarly, the differences in measured diffusion parameters between phantoms generated from normal and denervated muscle geometries are consistent with expected results from the literature and further support the idea that DLP-based 3D printing can be used to fabricate realistic skeletal muscle phantoms or constructs. However, although differences in T 2 relaxation and diffusion properties were found for the phantoms containing different concentrations of intra-and extracellular PBS, we were unable to identify differences in the regional diffusion of water.…”

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“…Microstructural and microfluidic changes associated with these conditions include fiber atrophy, fibrosis, edema, and increased sarcolemma permeability, all of which theoretically change diffusion of water in muscle. 7,[10][11][12][13] In vivo, the presence of increased extracellular water due to edema/inflammation in injured muscle has been shown to strongly effect and may dominate the diffusion signal even when concurrent microstructural changes have an opposing diffusion profile. 10,12,14,15 Increased extracellular water content is normally observed on MRI as an increase in the T 2 relaxation value of the tissue.…”

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Early Exposure to Environmental Toxin Contributes to Neuronal Vulnerability and Axonal Pathology in a Model of Familial ALS

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