Examining the role of PPARβ/δ activation on skeletal muscle metabolism in the rodent model of Barth syndrome

Abstract

Background: Barth syndrome (BTHS) is an X-chromosome linked disease caused by mutated tafazzin, resulting in reduced remodelled cardiolipin and, in turn, impaired mitochondrial form and function. Skeletal muscle myopathy is a hallmark symptom of BTHS, where skeletal muscle weakness due to mitochondrial impairment leads to exercise intolerance and contributes to disease morbidity. Exercise interventions have demonstrated some improvements in muscle function, although complementary treatment strategies may yield further benefits. Activation of peroxisome proliferator activated receptor (PPAR)β/δ improves muscle function and exercise tolerance, partially through improved mitochondrial lipid oxidation. Using the Taz knockdown (TazKD) mouse model of BTHS, previous research has found that pan-PPAR agonism promotes exercise capacity and improved cardiac function. It is hypothesized that PPARβ/δ activation coupled with exercise will improve muscle contractile function and fatigue resistance, while promoting whole-body and skeletal muscle mitochondrial lipid metabolism in TazKD mice. Methods: 4–5-month-old male TazKD and wildtype littermates, with access to running wheels, received GW501516 (5 mg/kg/day), a PPARβ/δ specific agonist, or vehicle through intraperitoneal injections for 4 weeks. Voluntary wheel running, non-wheel activity, soleus contractile function and fatigability (in vitro contraction), mitochondrial respiration (high resolution respirometry), metabolic adaptations (metabolic caging), and body composition (DEXA) were quantified. Results: PPARβ/δ activation coupled with exercise promoted a decrease in relative fat mass, and preservation in relative lean mass while the respiratory exchange ratio (RER) remained unchanged within TazKD mice. Respirometry data demonstrated increased coupled respiration using both lipid and carbohydrate substrates, within skeletal muscle isolated mitochondria of treated TazKD mice. In vitro contraction revealed improvements in soleus relaxation rates with no change in time to peak twitch force, rate of force generation, and peak twitch force. Interestingly, PPARβ/δ activation also resulted in decreased force generation at various stimulation frequencies, and increased fatiguability within both wildtype and TazKD GW501516 treated groups. Conclusion: This study demonstrates the potential of PPARβ/δ activation coupled with exercise as a therapeutic strategy for mediating improvements in mitochondrial respiration within the skeletal muscle of TazKD mice. Improvements to skeletal muscle function remained limited to increased rates relaxation within soleus.