The Angiotensin Converting Enzyme Inhibitor Lisinopril Improves Muscle Histopathology but not Contractile Function in a Mouse Model of Duchenne Muscular Dystrophy.
BACKGROUND
Angiotensin converting enzyme inhibitors (ACEi) are the current standard of care treatment for cardiac dysfunction in Duchenne muscular dystrophy patients. We previously showed treatment with an ACEi plus mineralocorticoid receptor (MR) antagonist improves limb and respiratory skeletal muscles, in addition to cardiac muscles, in a dystrophic mouse model at 20 weeks-of-age.


OBJECTIVE
To determine whether previously observed preclinical benefits of an ACEi plus MR antagonist on dystrophic skeletal muscles can be reproduced by increasing ACEi dosage alone. We also compared functional and histological outcome measures at 10 and 20 weeks-of-age.


METHODS
Dystrophin deficient utrophin haplo-insufficient (utrn+/-;mdx) "het" mice were treated with 10, 20, or 50 mg/kg × day of the ACEi lisinopril from 4 to 10 weeks-of-age via water bottles and compared with C57BL/10 wild-type control mice and untreated hets. Data from 10 week-old het mice were also compared to data collected from an untreated het group at 20 weeks-old.In vivocardiac and grip strength measurements,in vitrodiaphragm andextensor digitorum longusmuscle force measurements, and histopathological analyses were performed. One-way ANOVA followed by Dunnettpost hoccomparison was used to determine significance.


RESULTS
ACEi treatment reduced skeletal muscle damage but had no significant effect on muscle force. Body weight, heart rate, grip strength and blood pressure were unaffected by treatment. Limb muscle histopathology was more informative at 10 than 20 weeks-of-age.


CONCLUSIONS
These results suggest increased ACEi dosage alone cannot improve all dystrophic parameters. Further optimization of MR antagonists in 20 week-old mice is warranted.
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA ; Department of Molecular & Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
Jeovanna
J
Lowe
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA ; Department of Molecular & Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
Andrew J
AJ
Wodarcyk
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Kyle T
KT
Floyd
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Neha
N
Rastogi
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Eric J
EJ
Schultz
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA ; Department of Molecular & Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
Sarah A
SA
Swager
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA ; Department of Molecular & Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
Jessica A
JA
Chadwick
Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, USA.
Tam
T
Tran
Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, USA.
Subha V
SV
Raman
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Paul M L
PM
Janssen
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA ; Department of Molecular & Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
Jill A
JA
Rafael-Fortney
Duchenne; Muscular dystrophy; abdominal muscle; angiotensin converting enzyme inhibitors; diaphragm; dystrophin; heart; lisinopril; mdx; mineralocorticoid receptor antagonists; quadriceps muscle; utrophin; young mice