The Effect of PPARβ/δ Activation on Soleus Contractile and Metabolic Function in the Rodent Model of Barth Syndrome

Abstract

Barth syndrome is a rare and incurable X-linked genetic disease that impairs the production of tafazzin (Taz) protein. Taz catalyzes the transacylation reaction of monolysocardiolipin (MLCL) in the final step of cardiolipin (CL) remodeling to produce biologically relevant tetralinolylcardiolipin (TLCL). CL is an integral phospholipid that is responsible for maintaining mitochondrial form and function. Mutations to the gene that encodes for Taz (TAZ) result in missing or decreased Taz enzymatic activity which lowers the quantity and quality of CL. This leads to mitochondrial dysfunction which produces the hallmark symptoms of Barth syndrome, namely cardiomyopathy, neutropenia (low white blood cells), and exercise intolerance stemming from skeletal muscle weakness. We have recently demonstrated that 8 weeks of supplemental linoleic acid treatment improves rates of contraction and relaxation of soleus in a rodent model of Barth syndrome, the Taz knockdown (KD) mouse. Interestingly, supplemental linoleic acid did not impact CL content or side chain composition. Thus, the mechanism underlying the improvements in contractile function are currently unknown, however, we hypothesize that these improvements may be a result of peroxisome proliferator-activated receptor (PPAR) β/δ activation via supplemental linoleic acid. PPARβ/δ is a transcriptional regulator that, when activated, increases mitochondrial biogenesis and oxidative capacity. Previous research has demonstrated that the activation of PPARβ/δ improves skeletal muscle function in wildtype mice (Chen et al., 2015; Narkar et al., 2008; Y.-X. Wang et al., 2004). Given that PPARβ/δ can be activated by free fatty acids, it is plausible that the improvements to contractile kinetics may be mediated through PPARβ/δ activation by linoleic acid. Thus, the purpose of this project is to investigate the role of PPARβ/δ in improving contractile kinetics in TazKD mice through increased mitochondrial biogenesis and improved oxidative metabolism.