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Omigapil treatment decreases fibrosis and improves respiratory rate in dy(2J) mouse model of congenital muscular dystrophy.

Yu Q, Sali A, Van der Meulen J, Creeden BK, Gordish-Dressman H, Rutkowski A, Rayavarapu S, Uaesoontrachoon K, Huynh T, Nagaraju K, Spurney CF - PLoS ONE (2013)

Bottom Line: There were no statistical differences in normalized forelimb grip strength between dy(2J) and controls at baseline or after 17.5 weeks and no significant differences seen among the dy(2J) treatment groups.Omigapil therapy (0.1 mg/kg) improved respiratory rate and decreased skeletal and respiratory muscle fibrosis in dy(2J) mice.These results support a putative role for the use of omigapil in laminin deficient congenital muscular dystrophy patients.

View Article: PubMed Central - PubMed

Affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington DC, United States of America.

ABSTRACT

Introduction: Congenital 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.

Methods: dy(2J) 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.

Results: dy(2J) mice treated with omigapil showed improved respiratory rates compared to vehicle treated dy(2J) 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 dy(2J) and controls at baseline or after 17.5 weeks and no significant differences seen among the dy(2J) treatment groups. At 30-33 weeks of age, dy(2J) mice treated with 0.1 mg/kg omigapil showed significantly more movement time and less rest time compared to vehicle treated. dy(2J) mice showed normal cardiac systolic function throughout the trial. dy(2J) 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. dy(2J) 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 dy(2J) mice demonstrated decreased apoptosis.

Conclusion: Omigapil therapy (0.1 mg/kg) improved respiratory rate and decreased skeletal and respiratory muscle fibrosis in dy(2J) mice. These results support a putative role for the use of omigapil in laminin deficient congenital muscular dystrophy patients.

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Apoptosis analysis of frozen tibialis anterior muscle with TUNEL assay on vehicle (A), Omigapil 0.1 mg/kg (B), Omigapil 1 mg/kg (C) treated dy2J and BL6 control (D) groups show vehicle treated dy2J mice had significantly more apoptosis than BL6 control (A, D, F; *P<0.05).Both Omigapil treated groups showed less apoptosis than vehicle treated group although statistically not different (A-C, F). BL6 slide treated with TACS-Nuclease was used as positive control (E).
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pone-0065468-g002: Apoptosis analysis of frozen tibialis anterior muscle with TUNEL assay on vehicle (A), Omigapil 0.1 mg/kg (B), Omigapil 1 mg/kg (C) treated dy2J and BL6 control (D) groups show vehicle treated dy2J mice had significantly more apoptosis than BL6 control (A, D, F; *P<0.05).Both Omigapil treated groups showed less apoptosis than vehicle treated group although statistically not different (A-C, F). BL6 slide treated with TACS-Nuclease was used as positive control (E).

Mentions: In the tibialis anterior, there was a significant increase in the percent TUNEL positive nuclei per field found in dy2J mice compared to controls (p<0.04). (Figure 2).


Omigapil treatment decreases fibrosis and improves respiratory rate in dy(2J) mouse model of congenital muscular dystrophy.

Yu Q, Sali A, Van der Meulen J, Creeden BK, Gordish-Dressman H, Rutkowski A, Rayavarapu S, Uaesoontrachoon K, Huynh T, Nagaraju K, Spurney CF - PLoS ONE (2013)

Apoptosis analysis of frozen tibialis anterior muscle with TUNEL assay on vehicle (A), Omigapil 0.1 mg/kg (B), Omigapil 1 mg/kg (C) treated dy2J and BL6 control (D) groups show vehicle treated dy2J mice had significantly more apoptosis than BL6 control (A, D, F; *P<0.05).Both Omigapil treated groups showed less apoptosis than vehicle treated group although statistically not different (A-C, F). BL6 slide treated with TACS-Nuclease was used as positive control (E).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675144&req=5

pone-0065468-g002: Apoptosis analysis of frozen tibialis anterior muscle with TUNEL assay on vehicle (A), Omigapil 0.1 mg/kg (B), Omigapil 1 mg/kg (C) treated dy2J and BL6 control (D) groups show vehicle treated dy2J mice had significantly more apoptosis than BL6 control (A, D, F; *P<0.05).Both Omigapil treated groups showed less apoptosis than vehicle treated group although statistically not different (A-C, F). BL6 slide treated with TACS-Nuclease was used as positive control (E).
Mentions: In the tibialis anterior, there was a significant increase in the percent TUNEL positive nuclei per field found in dy2J mice compared to controls (p<0.04). (Figure 2).

Bottom Line: There were no statistical differences in normalized forelimb grip strength between dy(2J) and controls at baseline or after 17.5 weeks and no significant differences seen among the dy(2J) treatment groups.Omigapil therapy (0.1 mg/kg) improved respiratory rate and decreased skeletal and respiratory muscle fibrosis in dy(2J) mice.These results support a putative role for the use of omigapil in laminin deficient congenital muscular dystrophy patients.

View Article: PubMed Central - PubMed

Affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington DC, United States of America.

ABSTRACT

Introduction: Congenital 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.

Methods: dy(2J) 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.

Results: dy(2J) mice treated with omigapil showed improved respiratory rates compared to vehicle treated dy(2J) 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 dy(2J) and controls at baseline or after 17.5 weeks and no significant differences seen among the dy(2J) treatment groups. At 30-33 weeks of age, dy(2J) mice treated with 0.1 mg/kg omigapil showed significantly more movement time and less rest time compared to vehicle treated. dy(2J) mice showed normal cardiac systolic function throughout the trial. dy(2J) 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. dy(2J) 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 dy(2J) mice demonstrated decreased apoptosis.

Conclusion: Omigapil therapy (0.1 mg/kg) improved respiratory rate and decreased skeletal and respiratory muscle fibrosis in dy(2J) mice. These results support a putative role for the use of omigapil in laminin deficient congenital muscular dystrophy patients.

Show MeSH
Related in: MedlinePlus