STIM1 R304W causes muscle degeneration and impaired platelet activation in mice

Area of Science:

• Cellular Physiology
• Molecular Biology
• Genetics

Background:

• STIM1 and ORAI1 are crucial for store-operated calcium entry (SOCE).
• Mutations in STIM1 can cause deleterious effects, exemplified by Stormorken syndrome.
• Understanding STIM1 gain-of-function mutations is vital for cellular and organ physiology.

Purpose of the Study:

• To investigate the physiological effects of the STIM1 R304W gain-of-function mutation in a mouse model.
• To explore the impact of this mutation on organ and cellular function, particularly SOCE.
• To understand how STIM1 expression levels influence disease phenotypes.

Main Methods:

• Generation of a mouse line expressing the STIM1 R304W gain-of-function mutation.
• Analysis of surviving mice for growth, skeletal muscle integrity, and exercise endurance.
• Assessment of cellular SOCE capacity in various tissues and cell types, including fibroblasts, megakaryocytes, and platelets.
• Utilisation of foetal liver chimeras to study STIM1 expression in haematopoietic cells.

Main Results:

• The STIM1 R304W mutation was lethal in homozygous mice; survivors exhibited reduced growth and skeletal muscle degeneration.
• Fibroblasts from mutant mice showed STIM1 downregulation, maintaining SOCE despite the mutation's constitutive activity.
• STIM1 protein was undetectable in homozygous megakaryocytes and platelets, leading to impaired platelet activation and absent SOCE.

Conclusions:

• Downregulation of STIM1 R304W in mice counteracted the gain-of-function phenotype, highlighting tissue-specific regulatory mechanisms.
• STIM1 plays a critical role in skeletal muscle development and integrity.
• The study underscores the complex interplay between STIM1 mutation, expression levels, and SOCE function in vivo.