Abstract
It is well known that spontaneously hypertensive rats (SHR) develop muscle pathologies with hypertension and heart failure, though the mechanism remains poorly understood. Woon et al. (2007) linked the circadian clock gene Bmal1 to hypertension and metabolic dysfunction in the SHR. Building on these findings, we compared the expression pattern of several core-clock genes in the gastrocnemius muscle of aged SHR (80 weeks; overt heart failure) compared to aged-matched control WKY strain. Heart failure was associated with marked effects on the expression of Bmal1, Clock and Rora in addition to several non-circadian genes important in regulating skeletal muscle phenotype including Mck, Ttn and Mef2c. We next performed circadian time-course collections at a young age (8 weeks; pre-hypertensive) and adult age (22 weeks; hypertensive) to determine if clock gene expression was disrupted in gastrocnemius, heart and liver tissues prior to or after the rats became hypertensive. We found that hypertensive/hypertrophic SHR showed a dampening of peak Bmal1 and Rev-erb expression in the liver, and the clock-controlled gene Pgc1α in the gastrocnemius. In addition, the core-clock gene Clock and the muscle-specific, clock-controlled gene Myod1, no longer maintained a circadian pattern of expression in gastrocnemius from the hypertensive SHR. These findings provide a framework to suggest a mechanism whereby chronic heart failure leads to skeletal muscle pathologies; prolonged dysregulation of the molecular clock in skeletal muscle results in altered Clock, Pgc1α and Myod1 expression which in turn leads to the mis-regulation of target genes important for mechanical and metabolic function of skeletal muscle.
Document Type
Article
Publication Date
11-4-2011
Digital Object Identifier (DOI)
http://dx.doi.org/10.1371/journal.pone.0027168
Repository Citation
Miyazaki, Mitsunori; Schroder, Elizabeth; Edelmann, Stephanie E.; Hughes, Michael E.; Kornacker, Karl; Balke, C. William; and Esser, Karyn A., "Age-Associated Disruption of Molecular Clock Expression in Skeletal Muscle of the Spontaneously Hypertensive Rat" (2011). Physiology Faculty Publications. 11.
https://uknowledge.uky.edu/physiology_facpub/11
Supporting documents
Notes/Citation Information
Published in PLoS ONE, v. 6, no. 11, e27168.
© 2011 Miyazaki 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.