Calsequestrin-1 Deficiency Induced Malignant Hyperthermia-Like Skeletal Injury through Mitochondrial Disorder

Area of Science:

• Muscle Physiology
• Mitochondrial Biology
• Genetics

Background:

• Calsequestrin-1 (CASQ1) is implicated in malignant hyperthermia (MH), a condition involving skeletal muscle dysfunction.
• Mitochondrial dysfunction is suspected in MH pathogenesis, but its underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the mechanisms of mitochondrial disorder in CASQ1 deficiency using a calsequestrin-1 knockout (Casq1-KO) mouse model.
• To elucidate the role of CASQ1 in skeletal muscle integrity and mitochondrial function.

Main Methods:

• Casq1-KO mice were used to assess skeletal muscle injury (grip strength, histology) and mitochondrial function (MMP, ATP, Ca2+).
• Oxidative stress was evaluated using Western blot and MDA assays.
• Adeno-associated virus serotype 9 (AAV9) carrying the CMV-Casq1 gene was used for gene transfection to assess functional recovery.

Main Results:

• Casq1-KO mice displayed significant skeletal muscle dysfunction, structural damage, and increased reactive oxygen species (ROS).
• Mitochondria from Casq1-KO mice showed reduced ATP production and membrane potential (MMP), with elevated mitochondrial Ca2+ levels.
• MICU1, a key mitochondrial Ca2+ regulator, was significantly downregulated in Casq1-KO skeletal muscle. Gene therapy with AAV9-CMV-Casq1 restored CASQ1 and MICU1 expression, improved mitochondrial function, and mitigated oxidative stress and injury.

Conclusions:

• CASQ1 deficiency directly induces skeletal muscle injury and myopathy.
• Reduced MICU1 expression, leading to increased mitochondrial Ca2+ and ROS, significantly contributes to the skeletal myopathy observed in MH-like syndromes due to CASQ1 dysfunction.