Hip region muscular dystrophy and emergence of motor deficits in dysferlin-deficient Bla/J mice.
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.
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina.
Nadia
N
Nagy
Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina.
Randal J
RJ
Nonneman
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina.
Telmo
T
Llanga
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina.
Catherine F
CF
Dial
Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina.
Natallia V
NV
Riddick
Mouse Specifics, Boston, Massachusetts.
Tom
T
Hampton
Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina.
Sheryl S
SS
Moy
Charles River Discovery, Kuopio, Finland.
Kimmo K
KK
Lehtimäki
Charles River Discovery, Kuopio, Finland.
Toni
T
Ahtoniemi
Charles River Discovery, Kuopio, Finland.
Jukka
J
Puoliväli
Jain Foundation, Inc., Seattle, Washington.
Hillarie
H
Windish
Jain Foundation, Inc., Seattle, Washington.
Douglas
D
Albrecht
Généthon [IR1] INSERM, U951, INTEGRARE Research Unit, Evry, France.
Isabelle
I
Richard
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina mhirsch@email.unc.edu.|Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina.
Matthew L
ML
Hirsch
D000818:Animals; D004195:Disease Models, Animal; D000073939:Dysferlin / Q000235:genetics*; D005260:Female; D005684:Gait / Q000502:physiology*; D006615:Hip / Q000000981:diagnostic imaging*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging* / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology
C497505:Dysf protein, mouse; D000073939:Dysferlin
Bla/J; dysferlin; locomotor deficits; mouse model; muscular MR imaging and spectroscopy