Why the study?
While cardiac manifestations of Barth syndrome are well characterized, the mechanisms underlying skeletal muscle weakness and fatigability are poorly understood.
Skeletal myopathy in Barth Syndrome appears to be driven by widespread neuromuscular remodeling and stress pathway activation rather than overt resting energetic failure.
Neuromuscular remodeling may drive Barth myopathy beyond energetic failure in mice; leaves open human translation and therapeutic targets.
Background: gene, which disrupts cardiolipin (CL) remodeling and mitochondrial function. While cardiac manifestations of BTHS are well characterized, the mechanisms underlying skeletal muscle weakness and fatigability are poorly understood. Methods: . This mutation preserves protein abundance but abolishes enzymatic activity. Skeletal muscle function was assessed via weightlifting and hanging tests. Muscle fiber composition and neuromuscular junction (NMJ) integrity were evaluated using immunofluorescence, western blotting, and in vivo electrophysiology. Mitochondrial morphology was examined by transmission electron microscopy, and bioenergetics were quantified using ultra-performance liquid chromatography. Stress signaling was assessed by western blotting. Results: mice exhibited elevated monolysocardiolipin and reduced mature CL levels, confirming deficient transacylase activity. These mice exhibited lower muscle strength and endurance, smaller muscle fibers of all types, and a shift toward fast-twitch type 2B fibers, which are more susceptible to fatigue. Electrophysiological analysis revealed a 60% reduction in motor unit number and an increase in average single motor unit potential, indicating motor neuron remodeling. NMJ protein analysis showed decreased MUSK and DOK7 and increased CHRNA1, suggesting impaired NMJ integrity. Despite mitochondrial structural abnormalities and reduced expression of key mitochondrial proteins (NDUFB8, MCU, TMEM65), resting ATP, phosphocreatine, and adenine nucleotide ratios were unchanged in both glycolytic and oxidative muscles. However, stress signaling pathways were markedly activated, including phosphorylation of eIF2α, increased CHOP, DELE1, p53 expression, and altered Wnt/β-catenin signaling components. Conclusions: Deficiency of Tafazzin enzymatic activity in skeletal muscle is sufficient to result in widespread neuromuscular remodeling, including fiber size/type shifts, motor unit loss, NMJ dysregulation, and stress pathway activation, without overt energetic failure at rest. These findings suggest that myopathy in BTHS arises not solely from mitochondrial ATP insufficiency but rather from cumulative structural and signaling disruptions.
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Matias et al. (2025) studied this question.
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