Key result
Myh11 mutations reduce force development in aortic smooth muscle vs wild-type tissues.
p-value: p=<0.01
Heterozygous mutations in Myh11 compromise contractile function primarily in aortic smooth muscle, providing a mechanistic basis for their association with human thoracic aortic disease.
Aortic-selective contractile impairment in Myh11 mutants is hypothesis-generating; leaves open relevance to human thoracic aortic disease.
Aortic smooth muscle contains limiting amounts of myosin light chain kinase (MLCK) for myosin regulatory light chain (RLC) phosphorylation and contraction that predisposes to thoracic aortic disease in humans containing heterozygous loss-of-function mutations in MYLK. We tested the hypothesis that thoracic aortic smooth muscle contraction may also be susceptible to variations in the smooth muscle-specific isoform of the motor protein myosin where inactivation of one Myh11 allele or the presence of one Myh11 missense variant associated with an increased risk of human aortic disease may result in a reduced force development response. Additionally, other kinds of smooth muscles may be less sensitive to the effects of mutations in one smooth muscle myosin allele, similar to results obtained with Mylk. Force development responses were reduced in aortic tissue from a conditional knockout of smooth muscle myosin heavy chain in adult mice (Myh11+/- or Myh11-/-) with a greater reduction with homozygous vs heterozygous tissues. Similar reductions in force responses were obtained with tissues containing either a heterozygous or homozygous knockin mutation in smooth muscle myosin heavy chain (Myh11+/R247C or Myh11R247C/R247C mutations that cause human aortic disease) with no significant changes in RLC phosphorylation. Agonist-dependent force responses were not reduced significantly in urinary bladder, ileal, or tracheal tissues from Myh11+/- mice while only ileal tissue showed a reduced force response in Myh11R247C/R247C mice. Thus, heterozygous mutations in Myh11 associated with reduced myosin function result in compromised contractile function primarily in aortic smooth muscle.
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Huang et al. (2018) studied Thoracic aortic disease. Myh11 gene mutations vs. Wildtype mice was evaluated on Aortic force development (p=<0.01). Heterozygous and homozygous mutations in the smooth muscle myosin heavy chain gene (Myh11) significantly reduced force development in aortic smooth muscle.
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