Novo ritmo cronobiológico descoberto em mamíferos

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The Swine Plasma Metabolome Chronicles "Many Days" Biological Timing and Functions Linked to Growth

Timothy G. Bromage , Youssef Idaghdour, Rodrigo S. Lacruz, Thomas D. Crenshaw, Olexandra Ovsiy, Björn Rotter, Klaus Hoffmeier, Friedemann Schrenk

Published: January 6, 2016DOI: 10.1371/journal.pone.0145919


The paradigm of chronobiology is based almost wholly upon the daily biological clock, or circadian rhythm, which has been the focus of intense molecular, cellular, pharmacological, and behavioral, research. However, the circadian rhythm does not explain biological timings related to fundamental aspects of life history such as rates of tissue/organ/body size development and control of the timing of life stages such as gestation length, age at maturity, and lifespan. This suggests that another biological timing mechanism is at work. Here we focus on a "many days" (multidien) chronobiological period first observed as enigmatic recurring growth lines in developing mammalian tooth enamel that is strongly associate with all adult tissue, organ, and body masses as well as life history attributes such as gestation length, age at maturity, weaning, and lifespan, particularly among the well studied primates. Yet, knowledge of the biological factors regulating the patterning of mammalian life, such as the development of body size and life history structure, does not exist. To identify underlying molecular mechanisms we performed metabolome and genome analyses from blood plasma in domestic pigs. We show that blood plasma metabolites and small non-coding RNA (sncRNA) drawn from 33 domestic pigs over a two-week period strongly oscillate on a 5-day multidien rhythm, as does the pig enamel rhythm. Metabolomics and genomics pathway analyses actually reveal two 5-day rhythms, one related to growth in which biological functions include cell proliferation, apoptosis, and transcription regulation/protein synthesis, and another 5-day rhythm related to degradative pathways that follows three days later. Our results provide experimental confirmation of a 5-day multidien rhythm in the domestic pig linking the periodic growth of enamel with oscillations of the metabolome and genome. This association reveals a new class of chronobiological rhythm and a snapshot of the biological bases that regulate mammalian growth, body size, and life history.

Citation: Bromage TG, Idaghdour Y, Lacruz RS, Crenshaw TD, Ovsiy O, Rotter B, et al. (2016) The Swine Plasma Metabolome Chronicles "Many Days" Biological Timing and Functions Linked to Growth. PLoS ONE 11(1): e0145919. doi:10.1371/journal.pone.0145919

Editor: Shin Yamazaki, University of Texas Southwestern Medical Center, UNITED STATES

Received: September 1, 2015; Accepted: December 10, 2015; Published: January 6, 2016

Copyright: © 2016 Bromage et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: Research support was provided by the 2010 Max Planck Research Award to TGB, endowed by the German Federal Ministry of Education and Research to the Max Planck Society ( and the Alexander von Humboldt Foundation ( in respect of the Hard Tissue Research Program in Human Paleobiomics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors BR and KH are employees of the commercial company "GenXPro GmbH", which performed the sncRNA genomics for the study, contributing their expertise as indicated in the Author Contributions.

Competing interests: Authors BR and KH were paid salary by the commercial company "GenXPro GmbH", during which time the funders provided fees for genomics services rendered. They innovated study design and measured concentrations of sncRNA, providing the raw data for analysis by the project team. This competing interest does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.