Omigapil Treatment Decreases Fibrosis and Improves Respiratory Rate in dy2J Mouse Model of Congenital Muscular Dystrophy

Abstract

IntroductionCongenital muscular dystrophy is a distinct group of diseases presenting with weakness in infancy or childhood and no current therapy. One form, MDC1A, is the result of laminin alpha-2 deficiency and results in significant weakness, respiratory insufficiency and early death. Modification of apoptosis is one potential pathway for therapy in these patients.Methodsdy2J mice were treated with vehicle, 0.1 mg/kg or 1 mg/kg of omigapil daily via oral gavage over 17.5 weeks. Untreated age matched BL6 mice were used as controls. Functional, behavioral and histological measurements were collected.Resultsdy2J mice treated with omigapil showed improved respiratory rates compared to vehicle treated dy2J mice (396 to 402 vs. 371 breaths per minute, p<0.03) and similar to control mice. There were no statistical differences in normalized forelimb grip strength between dy2J and controls at baseline or after 17.5 weeks and no significant differences seen among the dy2J treatment groups. At 30–33 weeks of age, dy2J mice treated with 0.1 mg/kg omigapil showed significantly more movement time and less rest time compared to vehicle treated. dy2J mice showed normal cardiac systolic function throughout the trial. dy2J mice had significantly lower hindlimb maximal (p<0.001) and specific force (p<0.002) compared to the control group at the end of the trial. There were no statistically significant differences in maximal or specific force among treatments. dy2J mice treated with 0.1 mg/kg/day omigapil showed decreased percent fibrosis in both gastrocnemius (p<0.03) and diaphragm (p<0.001) compared to vehicle, and in diaphragm (p<0.013) when compared to 1 mg/kg/day omigapil treated mice. Omigapil treated dy2J mice demonstrated decreased apoptosis.ConclusionOmigapil therapy (0.1 mg/kg) improved respiratory rate and decreased skeletal and respiratory muscle fibrosis in dy2J mice. These results support a putative role for the use of omigapil in laminin deficient congenital muscular dystrophy patients.

Behavioral and Locomotor Measurements Using an Open Field Activity Monitoring System for Skeletal Muscle Diseases

“…For example, when a larger sample size is used, as was done in the SJL study (see the second BL6 bar in Figures 3B, 3D, and 3E) significant differences between groups can be observed. The Dy2J animals also showed a complete loss of vertical activity levels, which mirrored their hindlimb paralysis, and in turn, an inability to rear (Figure 2B) 6 . Lastly, it is important to note the sex differences in the activity levels.…”

“…This is generally associated with decreased horizontal activity, vertical activity, total distance traveled and movement time, and increased rest time 5,6,12,17 . On the contrary, animals with unimpaired muscle function or those treated with therapeutics that decrease the progression of deteriorating muscle pathology are more likely to display higher activity levels 6,7,14,17 .…”

“…To show an example of typical results obtained using this protocol in animal models of neuromuscular disease, we provided data from a longitudinal study we previously conducted in the Dy2J congenital muscular dystrophy (CMD) animal model 6 . In short, the Dy2J model contains a truncated form of the LAMA2 gene that results in hindlimb paralysis, demyelination, and dystrophic skeletal muscle changes.…”

“…This SOP was previously validated 4 and published as a part of TREAT-NMD's SOPs for Duchenne muscular dystrophy (DMD) animal models 5 . We have used this methodology to phenotype and test the therapeutic efficacy of numerous drugs in a variety of animal models of neuromuscular disease, including Lama2 dy-2J /J (Dy2J) mice, the animal model for congenital muscular dystrophy (CMD) 6,7 . In turn, this article is adapted from our previously published TREAT-NMD SOP 5 .…”

“…The test is also widely used to assess anxiety like and exploratory behaviors [8][9][10] . In particular, the open field is a useful tool for assessing locomotive impairment in animal models of neuromuscular disease 11,12 and the efficacy of therapeutic drugs that may improve locomotion and/or motor function 6,7,13,14 . The open field activity assessment provides a different measure than muscle strength, which is commonly measured with grip strength, and it shows how drugs may affect other body systems (i.e.…”