Conditionally dominant negative impacts of clinically recessive TNNT1 myopathy mutations.

Abstract

TNNT1 nonsense mutation causing premature termination of the translation of slow skeletal muscle troponin T (ssTnT) has been reported with recessive inheritance and loss-of-function phenotypes. We studied the phenotypes of mouse models of Tnnt1 myopathies for pathological impacts besides the loss of slow fiber functions. Mice with a knock-in stop codon at Glu180 mimicking the Amish nemaline myopathy (ANM-KI) show similar recessive phenotypes to that of Tnnt1-knockout (ssTnT-KO) mice (Wei et al. J. Physiol. 2014) with loss of slow fibers, low fatigue-resistance, active regeneration, inflammatory immune cell infiltration and compensatory hypertrophy of fast fibers in slow fiber-rich muscles. ANM-KI mice showed significantly more loss of slow fibers, more active regeneration, worse post-fatigue recovery and more hypertrophy of fast fibers than that of ssTnT-KO mice at young age and advancing with age. A feature of TNNT1 premature termination mutations is decreased tropomyosin-binding affinity and loss of thin filament incorporation. Therefore, the more severe than ssTnT-KO myopathic phenotypes of ANM-KI mice suggest negative impacts of non-myofilament incorporated TnT fragment on causing degeneration of slow and mix fiber type muscles. Since hypertrophy of fast fibers was not seen in ANM-KI mice before 7 days of age when soleus muscle is not utilized due to premature neuromuscular development, work- and/or load-induced slow and mix fiber muscle injury may worsen the negative impacts by increasing the total level of non-myofilament incorporated TnT and fragments from the release of fast skeletal muscle TnT in mix type fibers. Since non-myofilament-incorporated TnT is rapidly degraded in normal muscle cells, the cytotoxic effect of non-myofilament-incorporated TnT and fragment may have high potency (Jeong et al. AJP, 2009) and this pathogenic mechanism presents a molecular target for the treatment of TNNT1 myopathies and for improving muscle health of carriers.