Analysis of spinal and muscle pathology in transgenic mice overexpressing wild-type and ALS-linked mutant MATR3

Mutations in MATR3 have been associated with amyotrophic lateral sclerosis (ALS) as well as a form of distal myopathy termed vocal cord pharyngeal distal myopathy (VCPDM). To begin to understand how mutations in MATR3 may cause disease, here we provide initial characterization of transgenic (Tg) mice expressing human wild-type (WT) MATR3 (MATR3(WT)) and ALS-mutant F115C MATR3 (MATR3(F115C)) proteins under the control of the mouse prion promoter (MoPrP). For each construct, we established multiple independent lines of mice that stably transmitted the transgene. Unexpectedly, for all stably-transmitting lines examined, MATR3 transgenic mRNA expression was more robust in muscle, with minimal expression in spinal cord. The levels of transgenic mRNA in muscle did not differ between mice from our lead MATR3(F115C) line and lead MATR3(WT) line, but mice from the lead MATR3(F115C) line had significantly higher levels of MATR3 protein in muscle over the lead MATR3(WT) line. Mice from the three independent, established lines of MATR3(F115C) mice developed weakness in both fore- and hind-limbs as early as <1months of age; whereas, MATR3(WT) mice aged to >20months were not overtly distinguishable from non-transgenic (NT) littermates based on basic motor phenotype. Muscle of both MATR3(WT) and MATR3(F115C) mice showed vacuoles by 2months of age which worsened by similar to 10months, but vacuolation was noticeably more severe in MATR3(F115C) mice. Overall, our results indicate that increasing the levels of MATR3 in muscle can cause pathologic changes associated with myopathy, with MATR3(F115C) expression causing overt muscle atrophy and a profound motor phenotype. The findings suggest that analysis of muscle pathology in individuals harboring ALS-linked MATR3 mutations should be routinely considered.