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- W2911225704 abstract "Multiple nonsense mutations have been found in TNNT1 gene to cause severe nemaline myopathies in various ethnic populations. TNNT1 gene encodes the slow skeletal muscle isoform of troponin T (ssTnT), a subunit of the sarcomeric regulatory protein. TNNT1 myopathies are clinically presented with recessive inheritance and the truncated fragment of ssTnT is not detectable in patient muscles due to the loss of myofilament incorporation. Since free TnT fragments are cytotoxic (Jeong et al., AJP 2009), here we studied a mouse model of Tnnt1 knock-in mutation E180X (ssTnT-KI) representing the Amish nemaline myopathy. Homozygotes of ssTnT-KI mice showed significantly decreased slow fibers in soleus muscle with poor fatigue resistance. Although no ssTnT fragment was detected in slow and mixed fiber type muscles, high numbers of centralized nuclei indicated active regeneration following injuries caused by the loss of functional ssTnT and/or cytotoxicity of the E180X fragment. An intriguing finding is significantly reduced number but prominent hypertrophy of fast fibers in soleus muscle of ssTnT-KImice. While this phenotype became more predominant during aging, no fast fiber loss or hypertrophy was seen in soleus muscle of ssTnT-KI mice at 7-day of age. Since ssTnT is not expressed in postnatal fast fibers, this observation suggests a secondary response to slow fiber injuries. Considering that this phenotype was not observed in Tnnt1 knockout mice, the expression of E180X truncated ssTnT may have cytotoxic effect in ssTnT-KI mouse muscles. The hypertrophy of fast fibers could serve as a compensatory adaptation to the loss of slow fiber functions.While the mechanism of compensatory adaptation remains further investigation, the cytotoxicity of the truncated ssTnT may be a circumstantial factor in the pathogenesis and pathophysiology of TNNT1 myopathy in both patients and carriers, suggesting a possible therapeutic target." @default.
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- W2911225704 date "2019-02-01" @default.
- W2911225704 modified "2023-10-16" @default.
- W2911225704 title "Cytotoxicity of Truncated Slow Skeletal Muscle Troponin T in TNNT1 Myopathies" @default.
- W2911225704 doi "https://doi.org/10.1016/j.bpj.2018.11.2086" @default.
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