Deficient Cardiolipin Remodelling Alters Muscle Fibre Composition and Neuromuscular Connectivity in Barth Syndrome - PubMed
6 hours ago
- #mitochondrial disorder
- #Barth syndrome
- #neuromuscular remodelling
- Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by mutations in the TAFAZZIN gene, leading to disrupted cardiolipin (CL) remodelling and mitochondrial dysfunction.
- A novel murine model (TazPM) with a patient-derived D75H point mutation in Tafazzin was studied, showing preserved protein abundance but abolished enzymatic activity.
- TazPM mice exhibited elevated monolysocardiolipin and reduced mature CL levels, resulting in lower muscle strength, endurance, and smaller muscle fibres with a shift towards fast-twitch type 2B fibres.
- Electrophysiological analysis revealed a 60% reduction in motor unit number and increased average single motor unit potential, indicating motor neuron remodelling.
- Neuromuscular junction (NMJ) protein analysis showed impaired integrity with decreased MUSK and DOK7 and increased CHRNA1.
- Despite mitochondrial structural abnormalities and reduced expression of key mitochondrial proteins, resting ATP and phosphocreatine levels were unchanged.
- Stress signalling pathways were markedly activated, including phosphorylation of eIF2α, increased CHOP, DELE1, p53 expression, and altered Wnt/β-catenin signalling.
- The study suggests that BTHS myopathy arises from cumulative structural and signalling adaptations rather than solely from mitochondrial ATP insufficiency.