Phenotypic Characterization of the Male Tafazzin-Knockout Mouse Model of Barth Syndrome at 3-, 6-, and 12-Months of Age

Abstract

Barth Syndrome (BTHS) is a devastating disorder caused by mutations in the gene encoding for Tafazzin (TAZ), a key enzyme involved in the biosynthesis of the phospholipid cardiolipin, which is vital for maintaining the structural integrity of the inner mitochondrial membrane. A deficiency of TAZ in BTHS results in mitochondrial dysfunction. This compromises the function of highly energetic tissues, and as a result, cardioskeletal myopathy is one of the most defining and incapacitating manifestations of BTHS. Metabolic abnormalities are a natural secondary complication of mitochondrial dysfunction and altered metabolism has been reported at multiple levels in BTHS, from mitochondrial to whole-body, and may play an important role in the pathogenesis of BTHS. Currently, there is no cure for this disease. As with all diseases, the development of novel therapeutics is aided by availability of a model that successfully recapitulates the major symptoms and outcomes of the human disease. In this regard, a novel mouse model of BTHS has recently been generated, the Taz-KO model. The cardiac phenotype of these mice has been studied in young animals, but other physiological and metabolic aspects have not yet been reported. Additionally, little is known about the phenotype of mice at older ages. In this thesis, I sought to characterize the physiological and functional phenotype of the Taz-KO mouse model pertaining to birth rate, growth, lifespan, gross anatomy, whole-body energy and substrate metabolism, exercise capacity and glucose homeostasis across aging in 3-, 6-, and 12-month-old male Taz-KO mice. This work demonstrates that the Taz-KO mouse model faithfully recapitulates important aspects of BTHS, including fetal and perinatal lethality, lean body mass deficiency, preference for glucose as a metabolic substrate, and progressive exercise intolerance. Additional findings that may yield mechanistic insight into the pathology of BTHS include increased whole-body energy expenditure, low adiposity, splenic atrophy with age and a shortened lifespan due to progression of disease. Therefore, the Taz-KO mouse model fulfills the critical need for a genetic model of BTHS that closely parallels the human syndrome.