Pathophysiological Effects of Overactive STIM1 on Murine Muscle Function and Structure

Area of Science:

• Cellular Biology
• Molecular Medicine
• Physiology

Background:

• Store-operated calcium entry (SOCE) is vital for cellular processes, regulated by STIM1 and ORAI1.
• Gain-of-function mutations in STIM1 and ORAI1 cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), leading to muscle weakness and multi-systemic issues.

Purpose of the Study:

• To investigate the pathophysiological effects of overactive SOCE on muscle function and structure.
• To identify molecular disease signatures and pathomechanisms in a TAM/STRMK mouse model.

Main Methods:

• Transcriptomics, morphological, and functional studies on a TAM/STRMK mouse model.
• In vivo investigations of muscle contraction and relaxation kinetics.
• Histological and respirometric analyses of muscle samples.

Main Results:

• Muscles from the mouse model showed aberrant gene expression in calcium handling and excitation-contraction coupling (ECC).
• Delayed muscle contraction and relaxation kinetics were observed.
• Signs of reticular stress, abnormal mitochondrial activity, enhanced myofiber degeneration, and reduced mitochondrial respiration were identified.

Conclusions:

• Overactive SOCE leads to significant muscle dysfunction and structural damage.
• A molecular disease signature and pathomechanism for TAM/STRMK muscle anomalies were deciphered.