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

Autor: Hiyoshi T; Neuroscience Translational Medicine, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan., Zhao F; Center of Excellence for Imaging, Preclinical and Translational Sciences, Takeda Development Center Americas, Inc., 95 Hayden Avenue, Lexington, MA, 02141, USA., Baba R; Muscular Disease and Neuropathy Unit, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan., Hirakawa T; Muscular Disease and Neuropathy Unit, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan., Kuboki R; Muscular Disease and Neuropathy Unit, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan., Suzuki K; Muscular Disease and Neuropathy Unit, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan., Tomimatsu Y; Neuroscience Translational Medicine, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan., O'Donnell P; Neuroscience Translational Medicine, Neuroscience Drug Discovery Unit, Takeda Development Center Americas, Inc., 95 Hayden Avenue, Lexington, MA, 02141, USA., Han S; Neuroscience Therapeutic Area Unit, Takeda Development Center Americas, Inc., 95 Hayden Avenue, Lexington, MA, 02141, USA., Zach N; Neuroscience Translational Medicine, Neuroscience Drug Discovery Unit, Takeda Development Center Americas, Inc., 95 Hayden Avenue, Lexington, MA, 02141, USA., Nakashima M; Neuroscience Translational Medicine, Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan. masato.nakashima@takeda.com.
Jazyk: angličtina
Zdroj: Skeletal muscle [Skelet Muscle] 2023 Nov 18; Vol. 13 (1), pp. 19. Date of Electronic Publication: 2023 Nov 18.
DOI: 10.1186/s13395-023-00331-1
Abstrakt: Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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