Non-invasive MRI and spectroscopy of mdx mice reveal temporal changes in dystrophic muscle imaging and in energy deficits.
In Duchenne muscular dystrophy (DMD), a genetic disruption of dystrophin protein expression results in repeated muscle injury and chronic inflammation. Magnetic resonance imaging shows promise as a surrogate outcome measure in both DMD and rehabilitation medicine that is capable of predicting clinical benefit years in advance of functional outcome measures. The mdx mouse reproduces the dystrophin deficiency that causes DMD and is routinely used for preclinical drug testing. There is a need to develop sensitive, non-invasive outcome measures in the mdx model that can be readily translatable to human clinical trials. Here we report the use of magnetic resonance imaging and spectroscopy techniques for the non-invasive monitoring of muscle damage in mdx mice. Using these techniques, we studied dystrophic mdx muscle in mice from 6 to 12 weeks of age, examining both the peak disease phase and natural recovery phase of the mdx disease course. T2 and fat-suppressed imaging revealed significant levels of tissue with elevated signal intensity in mdx hindlimb muscles at all ages; spectroscopy revealed a significant deficiency of energy metabolites in 6-week-old mdx mice. As the mdx mice progressed from the peak disease stage to the recovery stage of disease, each of these phenotypes was either eliminated or reduced, and the cross-sectional area of the mdx muscle was significantly increased when compared to that of wild-type mice. Histology indicates that hyper-intense MRI foci correspond to areas of dystrophic lesions containing inflammation as well as regenerating, degenerating and hypertrophied myofibers. Statistical sample size calculations provide several robust measures with the ability to detect intervention effects using small numbers of animals. These data establish a framework for further imaging or preclinical studies, and they support the development of MRI as a sensitive, non-invasive outcome measure for muscular dystrophy.
Center for Genetic Medicine Research, Children's National Medical Center, Washington, D.C., United States of America.
Christopher R
CR
Heier
Center for Genetic Medicine Research, Children's National Medical Center, Washington, D.C., United States of America.
Alfredo D
AD
Guerron
Department of Radiology, Howard University College of Medicine, Washington, D.C., United States of America.
Alexandru
A
Korotcov
Department of Radiology, Howard University College of Medicine, Washington, D.C., United States of America.
Stephen
S
Lin
Center for Genetic Medicine Research, Children's National Medical Center, Washington, D.C., United States of America; Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, D.C., United States of America.
Heather
H
Gordish-Dressman
Department of Diagnostic Imaging and Radiology, Children's National Medical Center, Washington, D.C., United States of America.
Stanley
S
Fricke
Department of Radiology, Children's National Medical Center, Washington, D.C., United States of America.
Raymond W
RW
Sze
Center for Genetic Medicine Research, Children's National Medical Center, Washington, D.C., United States of America; Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, D.C., United States of America.
Eric P
EP
Hoffman
Department of Radiology, Howard University College of Medicine, Washington, D.C., United States of America; Department of Electrical Engineering, Fu Jen Catholic University, Taipei, Taiwan.
Paul
P
Wang
Center for Genetic Medicine Research, Children's National Medical Center, Washington, D.C., United States of America; Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, D.C., United States of America.
Kanneboyina
K
Nagaraju
D000367:Age Factors; D000818:Animals; D018450:Disease Progression; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D013997:Time Factors