178 - Conditional striated muscle tafazzin knockout mouse model of Barth syndrome

Saturday, April 29, 2023

3:30 PM – 6:00 PM ET

Poster Number: 178
Publication Number: 178.218

Erika Yazawa, Boston Children's Hospital, Boston, MA, United States; Suya Wang, Boston Children's Hospital, Boston, MA, United States; Qing Ma, Boston Children's Hospital, Boston, MA, United States; Erin M. Keating, Boston Children's Hospital, Boston, MA, United States; William T.. Pu, Boston Children's Hospital, Boston, MA, United States

Presenting Author(s)

Erika Yazawa, MD (she/her/hers)

Neonatal-Perinatal Medicine Fellow
Boston Children's Hospital
Boston, Massachusetts, United States

Background: Barth syndrome (BTHS) is an X-linked recessive disorder caused by a mutation of the gene Tafazzin (TAZ) which leads to cardiomyopathy, skeletal myopathy, and neutropenia. Tafazzin catalyzes the transacylation of cardiolipin, a phospholipid critical to the inner mitochondrial membrane. Studies of Taz function in skeletal muscle and its rescue by AAV-Taz gene therapy have been limited by the lack of a skeletal muscle knockout model with a strong phenotype yet normal postnatal survival.

Objective: To establish a skeletal muscle tafazzin knockout model with normal postnatal survival, we used MCK-Cre to knockout Tafazzin in striated muscle.

Design/Methods:

MCK-Cre mice use the MCK promoter to achieve cardiac and skeletal muscle-specific Cre recombinase expression. Taz^Flox/YMCK-Cre mice were generated by crossing MCK-Cre males with Taz^Flox/Floxfemales containing a loxP-flanked tafazzin gene. Taz^Flox/YMCK-Cre-negative mice were used as controls. Skeletal and cardiac muscle were collected at P21 for TAZ and Cre quantification. Heart function and skeletal muscle function were measured by echocardiography and exercise treadmill testing, respectively.

Results:

No difference in survival or body weight was observed between control and KO mice at age 8 weeks. Taz^Flox/Y MCK-Cre male mice have reduced fractional shortening (FS) at 8 weeks of age compared to control littermates (P=0.02), consistent with progressive cardiomyopathy that we previously observed in mice with a cardiac-specific knockout. Mutant and control mice had similar treadmill endurance at 8 weeks. We will test for progressive loss of treadmill endurance by performing the treadmill assay monthly.

Conclusion(s): Taz^Flox/Y MCK-Cre male mice have a Cre-conditional tafazzin knockout allele and develop cardiac dysfunction by 2 months of age. Future analyses will measure biochemical markers of tafazzin knockout and determine if the mutant mice develop progressive skeletal muscle dysfunction.