Electrical impedance myography detects dystrophin-related muscle changes in mdx mice

• Published in: Skeletal muscle Vol. 13; no. 1; p. 19
• Main Authors: Hiyoshi, Tetsuaki, Zhao, Fuqiang, Baba, Rina, Hirakawa, Takeshi, Kuboki, Ryosuke, Suzuki, Kazunori, Tomimatsu, Yoshiro, O'Donnell, Patricio, Han, Steve, Zach, Neta, Nakashima, Masato
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18-11-2023; BioMed Central; BMC
• Subjects: Age; Animals; Atrophy; Biomarkers; Cell-penetrating peptide conjugated antisense phosphorodiamidate morpholino oligomer; Clinical medicine; Clinical trials; Connective tissues; Duchenne muscular dystrophy; Duchenne's muscular dystrophy; Dystrophin; Dystrophin - genetics; Dystrophin - metabolism; Electric Impedance; Electric impedance myography; Electrical impedance; Ethylenediaminetetraacetic acid; Exon skipping; Histopathology; Inflammation; Limbs; Magnetic resonance imaging; Magnetic resonance spectroscopy; mdx mice; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Morpholinos - pharmacology; Morpholinos - therapeutic use; Muscle, Skeletal - metabolism; Muscles; Muscular dystrophy; Muscular Dystrophy, Duchenne - diagnostic imaging; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - pathology; Musculoskeletal system; Mutation; Myography; Nuclear magnetic resonance spectroscopy; Peptides; Scientific equipment and supplies industry; Signal to noise ratio; Skeletal muscle; Utrophin; United States; Japan; United States > US; Electric impedance myography; Magnetic resonance imaging; Cell-penetrating peptide conjugated antisense phosphorodiamidate morpholino oligomer; Duchenne muscular dystrophy; mdx mice
• ISSN: 2044-5040; 2044-5040
• DOI: 10.1186/s13395-023-00331-1

The lack of functional dystrophin protein in Duchenne muscular dystrophy (DMD) causes chronic skeletal muscle inflammation and degeneration. Therefore, the restoration of functional dystrophin levels is a fundamental approach for DMD therapy. Electrical impedance myography (EIM) is an emerging tool that provides noninvasive monitoring of muscle conditions and has been suggested as a treatment response biomarker in diverse indications. Although magnetic resonance imaging (MRI) of skeletal muscles has become a standard measurement in clinical trials for DMD, EIM offers distinct advantages, such as portability, user-friendliness, and reduced cost, allowing for remote monitoring of disease progression or response to therapy. To investigate the potential of EIM as a biomarker for DMD, we compared longitudinal EIM data with MRI/histopathological data from an X-linked muscular dystrophy (mdx) mouse model of DMD. In addition, we investigated whether EIM could detect dystrophin-related changes in muscles using antisense-mediated exon skipping in mdx mice.
The MRI data for muscle T2, the magnetic resonance spectroscopy (MRS) data for fat fraction, and three EIM parameters with histopathology were longitudinally obtained from the hindlimb muscles of wild-type (WT) and mdx mice. In the EIM study, a cell-penetrating peptide (Pip9b2) conjugated antisense phosphorodiamidate morpholino oligomer (PPMO), designed to induce exon-skipping and restore functional dystrophin production, was administered intravenously to mdx mice.
MRI imaging in mdx mice showed higher T2 intensity at 6 weeks of age in hindlimb muscles compared to WT mice, which decreased at ≥ 9 weeks of age. In contrast, EIM reactance began to decline at 12 weeks of age, with peak reduction at 18 weeks of age in mdx mice. This decline was associated with myofiber atrophy and connective tissue infiltration in the skeletal muscles. Repeated dosing of PPMO (10 mg/kg, 4 times every 2 weeks) in mdx mice led to an increase in muscular dystrophin protein and reversed the decrease in EIM reactance.
These findings suggest that muscle T2 MRI is sensitive to the early inflammatory response associated with dystrophin deficiency, whereas EIM provides a valuable biomarker for the noninvasive monitoring of subsequent changes in skeletal muscle composition. Furthermore, EIM reactance has the potential to monitor dystrophin-deficient muscle abnormalities and their recovery in response to antisense-mediated exon skipping.