Ryanodine receptor type 1 content decrease-induced endoplasmic reticulum stress is a hallmark of myopathies.

Area of Science:

• Muscle physiology and molecular biology
• Cellular stress responses
• Neuromuscular disease mechanisms

Background:

• Decreased ryanodine receptor type 1 (RyR1) protein is a hallmark of recessive RYR1-related myopathies.
• The role of RyR1 reduction in other myopathies and its underlying mechanisms remain less understood.

Purpose of the Study:

• To investigate RyR1 protein levels in various myopathies beyond RYR1-related disorders.
• To elucidate the molecular mechanisms by which reduced RyR1 protein contributes to muscle pathology.

Main Methods:

• Analysis of publicly available datasets and human muscle samples from inflammatory and mitochondrial myopathies.
• Utilized an inducible muscle-specific RYR1 recessive mouse model and RyR1 knockdown in C2C12 muscle cells.
• Employed proteomics, lipidomics, molecular biology, and electron microscopy to assess RyR1 reduction effects.

Main Results:

• Reduced RYR1 transcripts and protein levels were observed in necrotizing myopathy, inclusion body myopathy, polymyositis, dermatomyositis, myotonic dystrophy, Duchenne, Becker, and limb-girdle muscular dystrophies.
• RyR1 depletion in vitro and in vivo models led to decreased ER-mitochondria contact, impaired Ca2+ transfer, mitochondrial dysfunction, and accumulation of harmful sphingolipids.
• Increased endoplasmic reticulum (ER) stress markers (GRP78-Bip) and pro-apoptotic protein (CHOP-DDIT3) were consistently found in RyR1-deficient muscles.

Conclusions:

• Decreased RyR1 protein is a common feature across diverse myopathies, not limited to RYR1-related conditions.
• RyR1 depletion significantly contributes to myopathy pathogenesis through the induction of ER stress.
• These findings highlight ER stress as a critical mechanism linking RyR1 deficiency to muscle disorders.