Constitutive, Muscle-Specific Knockout Results in the Incomplete Assembly of Ca Entry Units and a Reduction in the Age-Dependent Formation of Tubular Aggregates.

Store-operated Ca entry (SOCE) is a ubiquitous cellular mechanism that cells use to activate extracellular Ca entry when intracellular Ca stores are depleted. In skeletal muscle, SOCE occurs within Ca entry units (CEUs), intracellular junctions between stacks of SR membranes containing STIM1 and transverse tubules (TTs) containing ORAI1. Gain-of-function mutations in and are linked to tubular aggregate (TA) myopathy, a disease characterized by the atypical accumulation of tubes of SR origin. Moreover, SOCE and TAs are increased in the muscles of aged male mice. Here, we assessed the longitudinal effects (from 4-6 months to 10-14 months of age) of constitutive, muscle-specific knockout (cOrai1 KO) on skeletal muscle structure, function, and the assembly of TAs and CEUs. The results from these studies indicate that cOrai1 KO mice exhibit a shorter lifespan, reduced body weight, exercise intolerance, decreased muscle-specific force and rate of force production, and an increased number of structurally damaged mitochondria. In addition, electron microscopy analyses revealed (i) the absence of TAs with increasing age and (ii) an increased number of SR stacks without adjacent TTs (i.e., incomplete CEUs) in cOrai1 KO mice. The absence of TAs is consistent with TAs being formed as a result of excessive ORAI1-dependent Ca entry.