Gain-of-Function STIM1 L96V Mutation Causes Myogenesis Alteration in Muscle Cells From a Patient Affected by Tubular...

Area of Science:

• Muscle physiology
• Calcium signaling
• Rare genetic disorders

Background:

• Tubular Aggregate Myopathy (TAM) is a rare genetic muscle disorder.
• It stems from mutations in STIM1 or ORAI1, affecting calcium (Ca2+) homeostasis.
• The precise mechanisms linking these mutations to muscle dysfunction are unclear.

Purpose of the Study:

• To investigate how Ca2+ dysregulation in TAM impacts muscle differentiation.
• To functionally characterize myoblasts and myotubes from patients with STIM1 L96V mutation.

Main Methods:

• Fura-2 cytofluorimetry for Ca2+ measurements.
• High-content imaging for cellular morphology.
• Real-time PCR for gene expression analysis.

Main Results:

• STIM1 mutant cells showed higher resting Ca2+ and increased Store-Operated Calcium-Entry (SOCE).
• Compensatory downregulation of Ca2+ handling genes (RyR1, Atp2a1, Trpc1) was observed.
• STIM1 mutant myoblasts exhibited impaired differentiation, with abnormal myotube morphology and mitochondrial networks.

Conclusions:

• Altered Ca2+ homeostasis in TAM disrupts myogenesis, particularly late differentiation.
• Gene expression analysis confirmed defects in myogenic and mitochondrial pathways.
• A reliable cellular model for TAM preclinical studies was validated.