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Published on: September 29, 2014
Development of outcome measures according to dystrophic phenotypes in canine X-linked muscular dystrophy in Japan
Mutsuki Kuraoka1,2, Yoshitsugu Aoki2, Shin'ichi Takeda3
1Laboratory of Experimental Animal Science, Nippon Veterinary and Life Science University, 1-7-1 Kyonancho, Musashino, Tokyo 180-8602, Japan.
Abstract:
Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disorder characterized by primary muscle degeneration. Therapeutic strategies for DMD have been extensively explored, and some are in the stage of human clinical trials. Along with the development of new therapies, sensitive outcome measures are needed to monitor the effects of new treatments. Therefore, we investigated outcome measures such as biomarkers and motor function evaluation in a dystrophic model of beagle dogs, canine X-linked muscular dystrophy in Japan (CXMDJ). Osteopontin (OPN), a myogenic inflammatory cytokine, was explored as a potential biomarker in dystrophic dogs over the disease course. The serum OPN levels of CXMDJ dystrophic dogs were elevated, even in the early disease phase, and this could be related to the presence of regenerating muscle fibers; as such, OPN would be a promising biomarker for muscle regeneration. Next, accelerometry, which is an efficient method to quantify performance in validated tasks, was used to evaluate motor function longitudinally in dystrophic dogs. We measured three-axis acceleration and angular velocity with wireless hybrid sensors during gait evaluations. Multiple parameters of acceleration and angular velocity showed notedly lower values in dystrophic dogs compared with wild-type dogs, even at the onset of muscle weakness. These parameters accordingly decreased with exacerbation of clinical manifestations along with the disease course. Multiple parameters also indicated gait abnormalities in dystrophic dogs, such as a waddling gait. These outcome measures could be applicable in clinical trials of patients with DMD or other muscle disorders.
Insights
New biomarkers and motor function tests show promise for monitoring Duchenne muscular dystrophy (DMD) treatments. Osteopontin (OPN) levels and accelerometry data in dystrophic dogs could aid clinical trials for muscle disorders.
Area of Science:
- Biomarkers and disease progression
- Translational research in neuromuscular disorders
Background:
- Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disorder requiring effective outcome measures for clinical trials.
- Current therapeutic strategies for DMD necessitate sensitive tools to monitor treatment efficacy.
Purpose of the Study:
- To investigate osteopontin (OPN) as a biomarker for muscle regeneration in canine X-linked muscular dystrophy (CXMDJ).
- To evaluate accelerometry for longitudinal assessment of motor function in dystrophic dogs.
- To identify reliable outcome measures for DMD clinical trials.
Main Methods:
- Serum osteopontin (OPN) levels were measured in CXMDJ dogs throughout the disease course.
- Wireless hybrid sensors were used to record three-axis acceleration and angular velocity during gait evaluations in CXMDJ and wild-type dogs.
- Analysis of gait parameters including acceleration and angular velocity to detect functional deficits.
Main Results:
- Elevated serum OPN levels were observed in CXMDJ dogs, correlating with muscle regeneration and indicating potential as a biomarker.
- Dystrophic dogs exhibited significantly lower acceleration and angular velocity parameters compared to wild-type dogs, even at early disease stages.
- Motor function parameters declined with disease progression, and gait abnormalities like a waddling gait were detected.
Conclusions:
- Osteopontin (OPN) shows potential as a sensitive biomarker for muscle regeneration in Duchenne muscular dystrophy.
- Accelerometry provides objective, quantitative data on motor function deficits and gait abnormalities in canine models of DMD.
- These outcome measures are promising for application in clinical trials for Duchenne muscular dystrophy and other muscle disorders.
