Muscular Dystrophy Efficacy Studies

JAX performs efficacy studies on mouse models for these diseases: C57BL10.mdx and D2.mdx for DMD, DyW for CMD1A, and A/J for dysferlinopathy. Additional mouse mutants are available for studies.

 

Efficacy studies performed by JAX® In Vivo Services evaluate muscle function with readouts such as rotarod performance, time to exhaustion with forced exercise, grip strength, and locomotor testing in response to therapeutics. Assessment of inflammation and fibrosis are new offerings to determine amelioration following treatment. Available tests include:

  • Rotarod tests motor coordination
  • Open field tests exploration
  • Grip strength
  • Force measurement measures the torque of the dorsiflexion of the foot with stimulation
  • Righting reflex
  • Forced exercise
  • Gait analysis
  • Dye uptake as a measure of muscle fibers damage or fibrosis
  • Serum biochemistry
  • Tissue (e.g. skeletal muscles) & blood collection
  • Cell sorting and quantification on immune cells infiltrating the muscles
  • Automated morphometry, immunohistochemistry, and detailed histopathology of muscles
  • Additional tests available upon request, please inquire

Example of DMD study design

  • The standard study utilizes B10.mdx (001801) and a control group of wild-type C57BL/10ScSnJ (000476).
  • Typically, 4-week old males are used with 10 mice per cohort.
  • Three test article arms, and one vehicle control arm from B10.mdx (001801), and one vehicle control arm from the wild-type control (000476).
  • Study duration is 5 weeks: 1 week acclimation and 4 weeks dosing.
  • Data collected during the study include:
    • 4 weeks of daily dosing and body weights.
    • Open field and serum creatine kinase assessment at the beginning and end of the study.
    • Necropsy with terminal serum or plasma collection, and harvesting of the tibialis anterior, gastrocnemius and diaphragm muscles with processing in formalin for fibrosis staining and quantification.

Comparison of Muscular Dystrophy Mouse Models

Strain Ambulation & Strength Serum CK Fibrosis Inflammation Morphometry
B10.mdx (001801) No loss Very High Mild Very high Hypertrophy
D2.mdx (013141) Loss High Severe High Atrophy
A/J (000646) No loss High Mild High Atrophy
DyW (013786) *
Severe loss High Severe High Atrophy
*Cryo recovery only

 

Duchenne Muscular Dystrophy (DMD) is one of the most common lethal genetic disease of childhood. It is an inherited X-linked disorder that results in the loss of or aberrant function of dystrophin, a protein involved in maintaining muscle integrity. Onset occurs in infancy and disease phenotypes include muscle weakness, loss of locomotion, and inflammation of the muscles. The following mouse models mimic various aspects of the human disease:

  • C57BL/10ScSn-Dmdmdx/J (001801) also known as B10.mdx
  • D2.B10-Dmdmdx/J (013141) also known as D2.mdx

View the publication Effect of genetic background on the dystrophic phenotype in mdx mice in the Oxford Journals.

Congenital Muscular Dystrophy onset occurs at birth. Disease phenotypes include diminished muscle tone and muscle degeneration. The following mouse models mimic various aspects of the human disease:

  • B6.129S1(Cg)-Lama2tm1Eeng/J (013786), also know as DyW is a model for MDC1A (merosin-deficient congenital muscular dystrophy)

Dysferlinopathy, or Limb-girdle muscular dystrophy type 2B (LGMD2B) onset occurs in young adults. The progressive muscle wasting is variable between patients. The following mouse models mimic various aspects of the human disease:

  • A/J (000646) is a model for LGMD2B

Hematoxylin & Eosin Stains on dystrophy mouse models

mdx_stain

Examples of necrosis and fibers atrophy (top, right), fat infiltration (bottom left) and inflammation (bottom right), hallmarks of the muscle disease in different strains. The pathology  of the B10.mdx (top left) is comparatively mild.