Hip region muscular dystrophy and emergence of motor deficits in dysferlin-deficient Bla/J mice.

Abstract

The identification of a dysferlin-deficient animal model that accurately displays both the physiological and behavior aspects of human dysferlinopathy is critical for the evaluation of potential therapeutics. Disease progression in dysferlin-deficient mice is relatively mild, compared to the debilitating human disease which manifests in impairment of particular motor functions. Since there are no other known models of dysferlinopathy in other species, locomotor proficiency and muscular anatomy through MRI (both lower leg and hip region) were evaluated in dysferlin-deficient B6.A-Dysfprmd /GeneJ (Bla/J) mice to define disease parameters for therapeutic assessment. Despite the early and progressive gluteal muscle dystrophy and significant fatty acid accumulation, the emergence of significant motor function deficits was apparent at approximately 1 year of age for standard motor challenges including the rotarod, a marble bury test, grip strength, and swimming speed. Earlier observations of decreased performance for Bla/J mice were evident during extended monitoring of overall exploration and rearing activity. Comprehensive treadmill gait analyses of the Bla/J model indicated significant differences in paw placement angles and stance in relation to speed and platform slope. At 18 months of age, there was no significant difference in the life expectancy of Bla/J mice compared to wild type. Consistent with progressive volume loss and fatty acid accumulation in the hip region observed by MRI, mass measurement of individual muscles confirmed gluteal and psoas muscles were the only muscles demonstrating a significant decrease in muscle mass, which is analogous to hip-girdle weakness observed in human dysferlin-deficient patients. Collectively, this longitudinal analysis identifies consistent disease parameters that can be indicators of efficacy in studies developing treatments for human dysferlin deficiency.

• Authors: Nadia Nagy, Randal J Nonneman, Telmo Llanga, Catherine F Dial, Natallia V Riddick, Tom Hampton, Sheryl S Moy, Kimmo K Lehtimäki, Toni Ahtoniemi, Jukka Puoliväli, Hillarie Windish, Douglas Albrecht, Isabelle Richard, Matthew L Hirsch
• Journal: Physiological reports (Physiol Rep) Vol. 5 Issue 6 (Mar 2017) ISSN: 2051-817X [Electronic] United States
• PMID: 28320887 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Chemical References

• Dysf protein, mouse
• Dysferlin

Topics

• Animals
• Disease Models, Animal
• Dysferlin (genetics)
• Female
• Gait (physiology)
• Hip (diagnostic imaging)
• Male
• Mice
• Mice, Knockout
• Motor Activity (physiology)
• Muscle, Skeletal (diagnostic imaging, physiopathology)
• Muscular Dystrophies (diagnostic imaging, genetics, physiopathology)
• Muscular Dystrophies, Limb-Girdle (diagnostic imaging, genetics, physiopathology)