Deficient Cardiolipin Remodelling Alters Muscle Fibre Composition and Neuromuscular Connectivity in Barth Syndrome

Area of Science:

• Biochemistry
• Cell Biology
• Genetics

Background:

• Barth syndrome (BTHS) is an X-linked mitochondrial disorder caused by TAFAZZIN gene mutations.
• It disrupts cardiolipin remodeling and mitochondrial function, with cardiac effects well-known but skeletal muscle issues poorly understood.

Purpose of the Study:

• Investigate neuromuscular and mitochondrial alterations in a novel murine model of BTHS.
• Elucidate mechanisms of skeletal muscle weakness and fatigability in BTHS.

Main Methods:

• Utilized a novel murine model (TazPM) with a patient-derived Tafazzin mutation.
• Assessed skeletal muscle function, fiber composition, neuromuscular junction integrity, mitochondrial bioenergetics, and stress signaling.

Main Results:

• Male TazPM mice showed impaired cardiolipin remodeling and reduced muscle strength/endurance.
• Observed muscle fiber atrophy, shifts to fatigable fiber types, motor unit loss, and NMJ dysregulation.
• Found activated stress signaling pathways despite normal resting energy levels.

Conclusions:

• Tafazzin deficiency causes significant neuromuscular remodeling and stress pathway activation in BTHS.
• Myopathy in BTHS results from structural and signaling adaptations, not solely mitochondrial ATP insufficiency.
• These findings highlight complex mechanisms underlying BTHS-associated myopathy.