A chemical chaperone improves muscle function in mice with a RyR1 mutation.

Area of Science:

• Muscle physiology
• Molecular genetics
• Biochemistry

Background:

• Mutations in the RYR1 gene are linked to severe muscle disorders.
• The specific mechanisms driving RYR1-related myopathies remain poorly understood.
• The I4895T mutation in RyR1 leads to muscle weakness and atrophy in mice.

Purpose of the Study:

• To investigate the molecular mechanisms underlying muscle dysfunction caused by the RYR1 I4895T mutation.
• To evaluate the therapeutic potential of the chemical chaperone 4-phenylbutyrate (4PBA) in a mouse model of RYR1 myopathy.

Main Methods:

• Characterization of sarcoplasmic reticulum (SR) Ca2+ handling, cellular stress markers, and mitochondrial function in RyR1 mutant mice.
• Assessment of muscle triadin content and calsequestrin (CSQ) localization.
• Treatment of mutant mice with 4PBA and evaluation of its effects on ER stress, muscle function, and SR Ca2+ transients.

Main Results:

• The I4895T mutation impaired SR Ca2+ transient amplitude, reduced resting cytosolic Ca2+ levels, decreased muscle triadin, and altered CSQ localization.
• Mutant mice exhibited increased endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and mitochondrial reactive oxygen species (ROS) production.
• 4PBA treatment ameliorated ER stress/UPR and improved muscle function, but did not fully restore SR Ca2+ transients.

Conclusions:

• The RYR1 I4895T mutation induces muscle pathology through mechanisms involving ER stress and altered Ca2+ handling.
• 4PBA demonstrates therapeutic promise for RYR1 myopathies associated with ER stress, independent of fully restoring Ca2+ release.
• Targeting ER stress pathways represents a viable therapeutic strategy for specific RYR1-related muscle diseases.