Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes

Area of Science:

• Mitochondrial biology
• Genetics
• Physiology

Background:

• Succinyl-CoA synthetase (SCS) deficiency is linked to mitochondrial encephalomyopathy.
• SCS is crucial for the TCA cycle and ATP production.
• Sucla2 is the ADP-specific beta subunit of SCS.

Purpose of the Study:

• To create and characterize a muscle-specific conditional knock-out (KO) mouse model of Sucla2.
• To investigate in vivo mechanisms of mitochondrial myopathy caused by Sucla2 deficiency.

Main Methods:

• Generated a muscle-specific Sucla2 KO mouse using Cre-Lox and CRISPR-Cas9.
• Validated gene and protein reduction via RT-qPCR and Western blot.
• Assessed in vivo phenotypes including body weight, grip strength, and exercise capacity.
• Performed ex vivo muscle contractility and histological analyses.

Main Results:

• Sucla2 KO mice exhibited significant reductions in Sucla2 transcript (68%) and protein (95%).
• Mice showed decreased body weight (44%), grip strength (34-40%), and exercise endurance (88%).
• Soleus (SOL) muscles displayed reduced force (40%), slower contraction/relaxation, increased mitochondria, and more Type 1 fibers compared to EDL muscles.

Conclusions:

• Sucla2 loss in skeletal muscle creates a viable model for SCS-deficient mitochondrial myopathy.
• The model demonstrates muscle weakness, reduced exercise tolerance, and distinct impacts on SOL vs. EDL muscles.
• This Sucla2 KO mouse is a valuable tool for studying muscle-specific and fiber-type-specific pathogenesis in mitochondrial myopathies.