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Exp Gerontol. 2018 Jul 15;108:35-40. doi: 10.1016/j.exger.2018.03.012. Epub 2018 Mar 27.

Troponin T3 associates with DNA consensus sequence that overlaps with p53 binding motifs.

Author information

1
Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL 32804, United States. Electronic address: Yury.Nunez-Lopez@flhosp.org.
2
Departments of Internal Medicine, Section of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
3
Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL 32804, United States.
4
Departments of Internal Medicine, Section of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States. Electronic address: odelbono@wakehealth.edu.

Abstract

We recently reported that in addition to its classical cytoplasmic location, the fast skeletal muscle Troponin T3 (TnT3) shuttles to the nucleus, where it appears to perform nonclassical transcription regulatory functions. Importantly, changes in the composition of the nucleus-localized pool of TnT3 and its fragments contribute to age-dependent muscle damage and wasting. Here, using ChIP-Seq, we demonstrate that TnT3 associates with DNA consensus sequences including the TGCCT motif, which is required for p53 binding to the promoter area of p53-related genes. Gene set enrichment analysis further demonstrated that the p53 pathway was the most significantly enriched pathway among genes annotated to the TnT3 ChIP-Seq peaks. We further demonstrated a strong correlation (r = 0.78, P = 1 × 10-4) between the expression levels of TNNT3 and TP53-inducible ribonucleotide reductase regulatory subunit M2B (RRM2B) in skeletal muscle tissue of 21 lean non-diabetic human subjects and a significant (P < 0.05) reduction in the levels of both gene transcripts in the third age-tertile group [42.3-70 years of age (yoa)] as compared to the second age-tertile (31.3-42.3 yoa). Of note, both TNNT3 and RRM2B expression levels negatively associated with total body fat mass (each with r = 0.49, P < 0.05), whereas RRM2B positively correlated with pancreatic β cell function (rRRM2B~HOMA-B = 0.47, P = 0.047). This work suggests that reduced TNNT3 gene expression is another mechanism leading to reduced TnT3 and excitation-contraction coupling with aging. Consequently, TnT3 appears to contribute to age-related sarcopenia and possibly other age-related deficiencies such as muscle insulin resistance and β cell dysfunction by interacting with TnT3-binding sequences in the promoter area of p53-related genes, among others, and consequently modulating the transcriptional regulation of these target genes.

KEYWORDS:

Aging; Calcium channel; Gene transcription; Skeletal muscle; Troponin T3

PMID:
29596868
PMCID:
PMC5994179
[Available on 2019-07-15]
DOI:
10.1016/j.exger.2018.03.012

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