title: Age-associated disruption of molecular clock expression in skeletal muscle of the spontaneously hypertensive rat.
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 In addition, the core-clock gene Clock and the muscle-specific, clock-controlled gene Myod1, no longer maintained a circadian pattern of expression in gastrocnemius from the hypertensive SHR.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.
authors.affiliation: Department of Physiology, Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Schroder
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Edelmann
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hughes
authors.forename: Karl
authors.initials: K
authors.lastname: Kornacker
authors.forename: C William
authors.initials: CW
authors.lastname: Balke
authors.forename: Karyn A
authors.initials: KA
authors.lastname: Esser
mesh_terms: D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D057906:Circadian Clocks / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C485975:DBP protein, rat; D004268:DNA-Binding Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D056926:CLOCK Proteins
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