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Fingerprinting Cardiolipin in Leukocytes by Mass Spectrometry for a Rapid Diagnosis of Barth Syndrome
Published on: March 23, 2022
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Deficient Cardiolipin Remodeling Alters Muscle Fiber Composition and Neuromuscular Connectivity in Barth Syndrome
Catalina Matias1,2, Paige L Snider3, Elizabeth A Sierra Potchanant3
1Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
Tafazzin deficiency in Barth syndrome causes skeletal muscle weakness through neuromuscular remodeling and stress pathway activation, not just energy depletion. This impacts motor units and neuromuscular junctions, leading to myopathy.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Barth syndrome (BTHS) is an X-linked mitochondrial disorder caused by mutations in the TAFAZZIN gene.
- TAFAZZIN mutations disrupt cardiolipin remodeling and mitochondrial function, leading to cardiac issues, but skeletal muscle defects are poorly understood.
Purpose of the Study:
- To investigate neuromuscular and mitochondrial alterations in a novel mouse model of BTHS with a patient-derived Tafazzin mutation (TazPM).
- To elucidate the mechanisms underlying skeletal muscle weakness and fatigability in BTHS.
Main Methods:
- Assessed skeletal muscle function using weightlifting and hanging tests in TazPM mice.
- Evaluated muscle fiber composition, neuromuscular junction (NMJ) integrity, and mitochondrial morphology.
- Quantified bioenergetics and analyzed stress signaling pathways via western blotting and ultra-performance liquid chromatography.
Main Results:
- TazPM mice showed reduced muscle strength, endurance, smaller fiber size, and a shift towards fatigable fiber types.
- Electrophysiology revealed motor unit loss and increased motor unit potential, indicating motor neuron remodeling.
- NMJ integrity was impaired, and stress signaling pathways were activated, despite normal resting energy levels.
Conclusions:
- Tafazzin deficiency causes significant neuromuscular remodeling and stress pathway activation in skeletal muscle.
- Myopathy in BTHS results from cumulative structural and signaling disruptions, not solely mitochondrial ATP insufficiency.
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