Phenotypic Characterization of Male Tafazzin -Knockout Mice at 3, 6, and 12 Months of Age.

Barth syndrome (BTHS) is an X-linked mitochondrial disease caused by mutations in the gene encoding for tafazzin (), a key enzyme in the remodeling of cardiolipin. Mice with a germline deficiency in have been generated (-KO) but not yet fully characterized. We performed physiological assessments of 3-, 6-, and 12-month-old male -KO mice, including measures of perinatal survival, growth, lifespan, gross anatomy, whole-body energy and substrate metabolism, glucose homeostasis, and exercise capacity. -KO mice displayed reduced viability, with lower-than-expected numbers of mice recorded at 4 weeks of age, and a shortened lifespan due to disease progression. At all ages, -KO mice had lower body weights compared with wild-type () littermates despite similar absolute food intakes. This finding was attributed to reduced adiposity and diminutive organs and tissues, including heart and skeletal muscles. Although there were no differences in basal levels of locomotion between age-matched genotypes, indirect calorimetry studies showed higher energy expenditure measures and respiratory exchange ratios in -KO mice. At the youngest age, -KO mice had comparable glucose tolerance and insulin action to mice, but while these measures indicated metabolic impairments in mice with advancing age that were likely associated with increasing adiposity, -KO mice were protected. Comparisons across the three age-cohorts revealed a significant and more severe deterioration of exercise capacity in -KO mice than in their littermate controls. The -KO mouse model faithfully recapitulates important aspects of BTHS, and thus provides an important new tool to investigate pathophysiological mechanisms and potential therapies.