The Circadian Clock within the Cardiomyocyte Is Essential for Responsiveness of the Heart to Fatty Acids

Abstract

Cells/organs must respond both rapidly and appropriately to increased fatty acid availability; failure to do so is associated with the development of skeletal muscle and hepatic insulin resistance, pancreaticβ-cell dysfunction, and myocardial contractile dysfunction. Here we tested the hypothesis that the intrinsic circadian clock within the cardiomyocytes of the heart allows rapid and appropriate adaptation of this organ to fatty acids by investigating the following: 1) whether circadian rhythms in fatty acid responsiveness persist in isolated adult rat cardiomyocytes, and 2) whether manipulation of the circadian clock within the heart, either through light/dark (L/D) cycle or genetic disruptions, impairs responsiveness of the heart to fasting in vivo. We report that both the intramyocellular circadian clock and diurnal variations in fatty acid responsiveness observed in the intact rat heart in vivo persist in adult rat cardiomyocytes. Reversal of the 12-h/12-h L/D cycle was associated with a re-entrainment of the circadian clock within the rat heart, which required 5–8 days for completion. Fasting rats resulted in the induction of fatty acid-responsive genes, an effect that was dramatically attenuated 2 days after L/D cycle reversal. Similarly, a targeted disruption of the circadian clock within the heart, through overexpression of a dominant negative CLOCK mutant, severely attenuated induction of myocardial fatty acid-responsive genes during fasting. These studies expose a causal relationship between the circadian clock within the cardiomyocyte with responsiveness of the heart to fatty acids and myocardial triglyceride metabolism. Cells/organs must respond both rapidly and appropriately to increased fatty acid availability; failure to do so is associated with the development of skeletal muscle and hepatic insulin resistance, pancreaticβ-cell dysfunction, and myocardial contractile dysfunction. Here we tested the hypothesis that the intrinsic circadian clock within the cardiomyocytes of the heart allows rapid and appropriate adaptation of this organ to fatty acids by investigating the following: 1) whether circadian rhythms in fatty acid responsiveness persist in isolated adult rat cardiomyocytes, and 2) whether manipulation of the circadian clock within the heart, either through light/dark (L/D) cycle or genetic disruptions, impairs responsiveness of the heart to fasting in vivo. We report that both the intramyocellular circadian clock and diurnal variations in fatty acid responsiveness observed in the intact rat heart in vivo persist in adult rat cardiomyocytes. Reversal of the 12-h/12-h L/D cycle was associated with a re-entrainment of the circadian clock within the rat heart, which required 5–8 days for completion. Fasting rats resulted in the induction of fatty acid-responsive genes, an effect that was dramatically attenuated 2 days after L/D cycle reversal. Similarly, a targeted disruption of the circadian clock within the heart, through overexpression of a dominant negative CLOCK mutant, severely attenuated induction of myocardial fatty acid-responsive genes during fasting. These studies expose a causal relationship between the circadian clock within the cardiomyocyte with responsiveness of the heart to fatty acids and myocardial triglyceride metabolism. It has long been appreciated that both experimental animals and humans exhibit diurnal variations in multiple cardiovascular parameters, including blood pressure, peripheral vascular resistance, heart rate, electrical properties of the heart (e.g. Q–T interval duration), and cardiac output (1Degaute J.P. Van Cauter E. van de Borne P. Linkowski P. Hypertension. 1994; 23: 244-253Crossref PubMed Scopus (60) Google Scholar, 2Degaute J.P. van de Borne P. Linkowski P. Van Cauter E. Hypertension. 1991; 18: 199-210Crossref PubMed Scopus (207) Google Scholar, 3Khatri I.M. Freis E.D. J. Appl. Physiol. 1967; 22: 867-873Crossref PubMed Scopus (212) Google Scholar, 4Millar-Craig M.W. Bishop C.N. Raftery E.B. Lancet. 1978; 1: 795-797Abstract PubMed Scopus (1147) Google Scholar, 5van den Buuse M. Physiol. Behav. 1999; 68: 9-15Crossref PubMed Scopus (53) Google Scholar, 6Veerman D.P. Imholz B.P. Wieling W. Wesseling K.H. van Montfrans G.A. Hypertension. 1995; 26: 55-59Crossref PubMed Scopus (140) Google Scholar, 7Zhang B.L. Zannou E. Sannajust F. Am. J. Physiol. 2000; 279: R169-R178Crossref PubMed Google Scholar). These rhythms have been ascribed primarily to fluctuations in neurohumoral influence during the day, which in turn are because of both environmental factors and the central circadian clock within the suprachiasmatic nucleus (8Turton M.B. Deegan T. Clin. Chim. Acta. 1974; 55: 389-397Crossref PubMed Scopus (279) Google Scholar, 9Prinz P.N. Halter J. Benedetti C. Raskind M. J. Clin. Endocrinol. Metab. 1979; 49: 300-304Crossref PubMed Scopus (160) Google Scholar, 10Richards A.M. Nicholls M.G. Espiner E.A. Ikram H. Cullens M. Hinton D. Clin. Exp. Hypertens. [A]. 1986; 8: 153-166Crossref PubMed Scopus (101) Google Scholar). Diurnal variations in physiological cardiovascular parameters have been attributed to the same factors (e.g. sympathetic activity) responsible for diurnal variations in fatal cardiovascular events, which have an increased incidence in the early hours of the morning (11Muller J.E. Tofler G.H. Stone P.H. Circulation. 1989; 79: 733-743Crossref PubMed Scopus (1267) Google Scholar, 12Mukamal K.J. Muller J.E. Maclure M. Sherwood J.B. Mittleman M.A. Am. Heart J. 2000; 140: 438-442Crossref PubMed Scopus (55) Google Scholar, 13Carson P.A. O'Connor C.M. Miller A.B. Anderson S. Belkin R. Neuberg G.W. Wertheimer J.H. Frid D. Cropp A. Packer M. J. Am. Coll. Cardiol. 2000; 36: 541-546Crossref PubMed Scopus (58) Google Scholar). However, few studies have investigated whether the intrinsic properties of the heart fluctuate during the day or whether a loss of synchronization between the presence of a stimulus (e.g. increased sympathetic activity in the early hours of the morning) and responsiveness of the heart plays a role in the instigation of contractile dysfunction. One extracellular influence that the heart must adapt to rapidly is a change in circulating fatty acid levels. Fatty acids are the primary fuel source for the normal myocardium, which generates ∼70% of the ATP required for contraction from fatty acid β-oxidation (14Lopaschuk G.D. Belke D.D. Gamble J. Itoi T. Schönekess B.O. Biochim. Biophys. Acta. 1994; 1213: 263-276Crossref PubMed Scopus (529) Google Scholar). However, fatty acids are more than just a fuel for cardiomyocytes because they act as both structural and signaling precursors (15Young M.E. McNulty P.H. Taegtmeyer H. Circulation. 2002; 105: 1861-1870Crossref PubMed Scopus (404) Google Scholar). As such, a balance between fatty acid availability and rates of fatty acid β-oxidation must be maintained. If the latter fails, detrimental fatty acid derivatives accumulate within the myocardium, which has been linked to the pathogenesis of various cardiomyopathies, including those observed in obese and diabetic subjects (15Young M.E. McNulty P.H. Taegtmeyer H. Circulation. 2002; 105: 1861-1870Crossref PubMed Scopus (404) Google Scholar, 16Unger R.H. Orci L. FASEB J. 2001; 15: 312-332Crossref PubMed Scopus (380) Google Scholar, 17Sharma S. Adrogue J.V. Golfman L. Uray I. Lemm J. Youker K. Noon G.P. Frazier O.H. Taegtmeyer H. FASEB J. 2004; 18: 1692-1700Crossref PubMed Scopus (624) Google Scholar). A major way in which the heart prevents accumulation of intramyocellular fatty acids during periods of increased availability is through induction of fatty acid-responsive genes that promote β-oxidation (15Young M.E. McNulty P.H. Taegtmeyer H. Circulation. 2002; 105: 1861-1870Crossref PubMed Scopus (404) Google Scholar, 18Barger P.M. Kelly D.P. Trends Cardiovasc. Med. 2000; 10: 238-245Crossref PubMed Scopus (416) Google Scholar). Increasing evidence exists in support of the hypothesis that the circadian clock intrinsic to the cardiomyocyte plays a critical role in synchronizing cardiac metabolism to the environment (19Durgan D.J. Hotze M.A. Tomlin C. E.D. M.E. Am. J. Physiol. PubMed Scopus Google Scholar, M.E. Am. J. Physiol. PubMed Scopus Google Scholar, M.A. M.E. Am. J. Physiol. 2004; PubMed Scopus Google Scholar, M.E. Hypertens. PubMed Scopus Google Scholar, M.E. P. A.M. P.H. Taegtmeyer H. 2001; PubMed Scopus Google Scholar). are of and negative with a of I. Physiol. 2000; PubMed Scopus Google Scholar). the of the to respond rapidly to a stimulus the appropriate of the day I. Physiol. 2000; PubMed Scopus Google Scholar). have been in a of including of the cardiovascular (19Durgan D.J. Hotze M.A. Tomlin C. E.D. M.E. Am. J. Physiol. PubMed Scopus Google Scholar, M.E. Am. J. Physiol. PubMed Scopus Google Scholar, G.D. M. Clin. Exp. Hypertens. PubMed Google Scholar, P. A. D. G.A. 2001; 105: PubMed Scopus Google Scholar). we the circadian clock within the cardiomyocytes of the rat heart (19Durgan D.J. Hotze M.A. Tomlin C. E.D. M.E. Am. J. Physiol. PubMed Scopus Google Scholar). adult rat cardiomyocytes adult rat fatty long cardiomyocyte CLOCK dominant negative in the presence of exhibit in for circadian clock (e.g. and These exhibit a of between and with to those observed in the intact heart in with the of a circadian clock within the cardiomyocyte (19Durgan D.J. Hotze M.A. Tomlin C. E.D. M.E. Am. J. Physiol. PubMed Scopus Google Scholar). fatty acid exhibit a diurnal with increased during the for As such, we that the circadian clock within the heart fatty acid availability circulating with the of the to this M.A. M.E. Am. J. Physiol. 2004; PubMed Scopus Google Scholar). a between parameters is observed in the increased circulating during the the rat heart increased of genes fatty acid during the increased responsiveness to fatty acids M.A. M.E. Am. J. Physiol. 2004; PubMed Scopus Google Scholar). of this was to the hypothesis that the circadian clock within the cardiomyocyte diurnal variations in the responsiveness of the heart to fatty the of both in and in vivo we report evidence in support of this 1) of responsiveness of cardiomyocytes to fatty acids and 2) disruption of the circadian clock within the heart in vivo. the circadian diurnal variations in the responsiveness of cardiomyocytes to fatty acids persist in disruption of the circadian clock within the cardiomyocyte severely impairs responsiveness of the heart to fatty acids in vivo. These studies are the to a for the circadian clock within the cardiomyocytes of the of the rats and and light/dark (L/D) cycle was by of a to the which the turn Reversal of the L/D cycle is to a rapid of the central circadian clock within the suprachiasmatic by re-entrainment of peripheral circadian rates S. R. M. A. R. M. G.D. M. H. 2000; PubMed Scopus Google Scholar). whether manipulation of the L/D cycle the circadian clock within the heart responsiveness of this organ to fatty the experimental was as in rats day as 1) rats the normal L/D cycle and 2) rats to a in the L/D cycle the rats the in the latter was in the of the the day of the Fasting was that the responsiveness of the heart to increased circulating fatty acid be isolated from the day in 2 and long was to the of re-entrainment of the circadian clock within the isolated and days of the L/D for and to and isolated from rats and as (19Durgan D.J. Hotze M.A. Tomlin C. E.D. M.E. Am. J. Physiol. PubMed Scopus Google Scholar). in with 2 and was with a of of to for 2 with or as the cardiomyocytes with with or as 2 with or as and in or as a of was to and to in an of for 2 to of a within a multiple and to of with a of a dominant negative CLOCK cardiomyocyte CLOCK in which a clock to the acids of the CLOCK and a was was by the to cardiomyocytes in the of a dominant negative was as to a because of the of of the circadian clock (e.g. a CLOCK is as in the heart as CLOCK and CLOCK is M.E. Am. J. Physiol. PubMed Scopus Google Scholar). studies in to the CLOCK a dominant negative effect CLOCK and and and for in of the the from of of was by and and P. Scopus Google Scholar, P.M. PubMed Scopus Google Scholar, J. K.J. P.M. PubMed Scopus Google Scholar). from rat and in for circadian clock genes output and muscle and 2 circadian genes and fatty acid-responsive genes and triglyceride metabolism genes 2 triglyceride and and and for have been with the of and which are in M.E. P. Taegtmeyer H. 2001; PubMed Scopus Google Scholar, M.E. S. J. C. Taegtmeyer H. FASEB J. 2001; 15: PubMed Scopus Google Scholar). clock was to for both clock and the are as of because of the of for isolated cardiomyocytes intact in of is of is for cardiomyocyte intact heart are as of studies investigating are to the to for in latter is because of the for which a as with to and in in a to heart of blood was from was to for a was and with a for to for triglyceride was from as H. Am. J. Physiol. 2002; Google Scholar). CLOCK and in heart by a to and with a that the of both the CLOCK and was a by through was in environment as by the to to and to experimental a was A A was to the of for in with the hypothesis of a We a the was than of was to the of or experimental and in was for this A including was for of hypothesis of was was because of the that in from Reversal of the Heart to investigated whether the circadian clock responsiveness of the heart to circulating fatty by the cardiomyocyte circadian clock in vivo through of the L/D myocardial circadian for clock in and genes exhibit circadian in in the intact rat heart of with that of the L/D the circadian clock within the heart to environment days a exists between and for the clock genes of with an re-entrainment of the circadian clock within the heart by days of the L/D a for clock genes of the circadian clock genes is in of re-entrainment of the circadian clock was by fasting of L/D cycle manipulation myocardial and in L/D cycle was as and and as in genes investigated and and are as the for are as of of are as and and and of L/D cycle manipulation myocardial and in L/D cycle was as and and as in genes investigated and and are as the for are as of of are as and and and and myocardial circadian for fatty acid-responsive genes in As fasting a induction in both and in of and and a more rapid induction of and with of and and in to a in and induction of and in was to that observed in an and and of fatty acid-responsive genes in and the of re-entrainment of the circadian clock within the heart of the L/D cycle was to the of of the responsiveness of the heart to fasting. that the of the stimulus fatty for and rats was in the induction of fatty acid-responsive genes during of was associated with a rapid in in investigated of within of between the investigated Diurnal in the of to Fatty in of the L/D cycle circadian within the as as normal rhythms in multiple neurohumoral to the influence of the circadian clock neurohumoral as of diurnal variations in the responsiveness of the heart to fatty These as 1) of isolated adult rat cardiomyocytes in and 2) of a CLOCK with for 2 has been to circadian clock in isolated (19Durgan D.J. Hotze M.A. Tomlin C. E.D. M.E. Am. J. Physiol. PubMed Scopus Google Scholar). As such, isolated with circadian in the of the clock genes investigated and in the of in in for in the of in as with those cardiomyocytes to circadian clock persist in in the presence of in circadian clock genes by the presence of the fatty acid in the However, cardiomyocytes with a rapid induction of and in both the and presence of (e.g. and induction of and within 2 for cardiomyocytes with and cardiomyocytes in the of induction of and a after and of fatty acid-responsive genes and for cardiomyocytes with a rapid induction of and in to was by a and a induction and in the of the of induction of this fatty acid-responsive was as during the induction as observed for the induction A after and These that diurnal variations in the responsiveness of cardiomyocytes to fatty acids in in which the circadian clock is in the presence of of studies in to the CLOCK a dominant negative effect CLOCK and and As such, with the of a of the resulted in a of activity of clock and genes an in activity latter was by of the in and the is in of both clock and was in and isolated from and a of the within the of the is than in both and of to clock was observed the of the was than CLOCK A was observed in of the within the cardiomyocytes of the heart was associated with of the circadian clock was investigated by circadian of clock as as fatty acid-responsive genes, in in the of clock and fatty acid-responsive genes investigated isolated from of with the loss of negative of the circadian in and to be in and in the clock output attenuated in of activity) was increased in As such, in the of circadian clock dramatically attenuated in as in and of the circadian clock genes and was between and for and of and in isolated from and are as the for are as of of that the influence the circadian clock in a of clock genes was investigated in and both and clock genes of observed in as observed in in for the fatty acid-responsive genes and and that of a dominant negative CLOCK in the cardiomyocytes of the heart in of the circadian clock within the heart, in a of circadian clock within circadian within of the heart (e.g. vascular muscle and that of the within the of to role for the circadian clock within the cardiomyocyte as a of the responsiveness of the heart to fatty acids was investigated through of the As rats in the L/D cycle manipulation and that the circadian clock was in both and in the and for either or as Fasting resulted in a induction of both myocardial and within with the in and for the rat heart, of fasting the in a induction of and of isolated from exhibit a in the induction of both and of the to resulted in a induction of and in fasting and in the induction of and in as as in that a circadian clock within the cardiomyocytes of the heart diurnal variations in the responsiveness of the heart to fatty the responsiveness of to the in myocardial triglyceride was between and We that induction of β-oxidation genes in during fasting in accumulation of myocardial Fasting increased triglyceride in by with However, fasting myocardial triglyceride in of and in an to the of triglyceride accumulation in during fasting A. R. C. J. R. C. S. D. M. R. PubMed Scopus Google Scholar, J.E. D. T. W. J.E. J. PubMed Scopus Google Scholar, P.M. J. 2004; 279: PubMed Scopus Google Scholar). for and circadian in with of and in and attenuated in was in with was of was between and in Fasting resulted in a induction of and as as a of in the of metabolism genes in These triglyceride metabolism genes as by the circadian clock within the they that the of triglyceride accumulation in is because of increased to of triglyceride metabolism genes in and and and in as and are as the for in are as of of and the same is the to a role for the circadian clock within the cardiomyocytes of the heart in vivo. We have the 1) of the circadian clock within the heart and of the responsiveness of the heart to fasting exhibit of the L/D 2) Diurnal variations in the responsiveness of the heart to fatty acids persist in the circadian clock is of the circadian clock within the cardiomyocyte genetic dramatically responsiveness of the heart to fasting. evidence that the circadian clock within the cardiomyocyte responsiveness of the heart to fatty to a that myocardial have the pathogenesis of cardiovascular observed during and within the Heart as a of have a between the circadian clock within the cardiomyocyte and myocardial metabolism. the of in we in of for both and (19Durgan D.J. Hotze M.A. Tomlin C. E.D. M.E. Am. J. Physiol. PubMed Scopus Google Scholar). in genes observed in in which the circadian clock was the same as observed in the intact heart in with circadian clock genes (19Durgan D.J. Hotze M.A. Tomlin C. E.D. M.E. Am. J. Physiol. PubMed Scopus Google Scholar). with the of and circadian in isolated from and we that circadian in of the triglyceride metabolism and are attenuated in that the circadian clock within the cardiomyocyte myocardial We have diurnal variations in the responsiveness of the heart to fatty with increased during the for the rat M.A. M.E. Am. J. Physiol. 2004; PubMed Scopus Google Scholar). with 2 the of and for during the whether diurnal variations in the responsiveness of the heart to fatty acids are because of diurnal variations in neurohumoral factors the intramyocellular circadian as 1) of responsiveness of cardiomyocytes to fatty acids and 2) disruption of the circadian clock within the heart in vivo. of circadian clock genes as a of the by the cardiomyocytes, in that diurnal variations in the responsiveness of cardiomyocytes to fatty acids persist vivo. in the intact rat heart in and for in and As such, a in the induction of fatty acid-responsive genes in is to in the intact rat is the which the responsiveness of the heart to fatty acids is observed in vivo in and Similarly, a in the induction of fatty acid-responsive genes is to in the intact rat is the the responsiveness of the heart to fatty acids is observed in vivo in and the of in both the circadian clock genes and the induction of fatty acid-responsive genes are observed in in the of diurnal variations in the responsiveness of the heart to fatty acids are in the circadian clock within the cardiomyocyte is disruption of the circadian clock within the heart, either through manipulation of the L/D cycle 2) or through of severely impairs responsiveness of the heart to fasting. These expose a causal relationship between the circadian clock within the heart and responsiveness of this organ to fatty fatty acid the of is during the for the responsiveness of the rat heart to fatty acids is during the of are the of the circadian clock within the that circadian of environmental the as to a exists between diurnal variations in fatty acid availability during the and responsiveness of the to fatty to that diurnal variations in fatty acid responsiveness be the of of of the the in the is in for a rapid induction of fatty acid this of fatty during M.E. Am. J. Physiol. PubMed Scopus Google Scholar, M.A. M.E. Am. J. Physiol. 2004; PubMed Scopus Google Scholar, M.E. Hypertens. PubMed Scopus Google Scholar). with this we that responsiveness of the heart to fasting is severely attenuated the circadian clock is the intramyocellular circadian clock to responsiveness of the heart to fatty acids has been in this Fatty acids rapidly through of a of as K. J. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). and to are within cardiomyocytes to with of and P.M. Kelly D.P. Trends Cardiovasc. Med. 2000; 10: 238-245Crossref PubMed Scopus (416) Google Scholar, L. W. Med. 2004; 10: PubMed Scopus Google Scholar, H. S. C. FASEB J. 2002; PubMed Scopus Google Scholar). with the to fatty within the of various genes K. D.J. PubMed Scopus Google Scholar). genes those fatty acid (e.g. and (e.g. M.E. S. J. C. Taegtmeyer H. FASEB J. 2001; 15: PubMed Scopus Google Scholar, P. Biophys. 2001; PubMed Scopus Google Scholar). to diurnal variations in the responsiveness of the heart to fatty the heart is more to the during the that of the circadian M.A. M.E. Am. J. Physiol. 2004; PubMed Scopus Google Scholar). we a induction of of the and in the rat heart during the M.A. M.E. Am. J. Physiol. 2004; PubMed Scopus Google Scholar). A. J.P. J. 1999; PubMed Scopus Google have that the circadian clock through of in the of with in are to those of M.A. M.E. Am. J. Physiol. 2004; PubMed Scopus Google Scholar). However, the observed responsiveness of to of that the circadian clock within the cardiomyocyte to fatty acid of the in the Heart with the in this that to the of re-entrainment of the circadian clock within the heart of the L/D 2 that the circadian clock within the heart between and days to of the L/D in the L/D cycle rapid of blood pressure, heart rate, and activity circadian rhythms in which are within days den Buuse M. Physiol. Behav. 1999; 68: 9-15Crossref PubMed Scopus (53) Google Scholar). that the circadian clock within the heart of is with the environment between and days of the L/D an re-entrainment of blood rhythms within the of the de R. E. J.P. Circulation. 1989; PubMed Google Scholar, S. A. A. J. Hypertens. PubMed Scopus Google Scholar). that the of re-entrainment for the circadian clock within the heart that of that the of the L/D by between the circadian clock within the heart and As such, of the of normal adaptation to diurnal variations in environmental neurohumoral factors and blood It is to that an in this increased of cardiovascular observed in subjects J.E. J. 1999; PubMed Scopus Google Scholar, A. T. K. Lancet. 1986; Scopus Google Scholar, M. PubMed Scopus Google Scholar). As with L/D cycle both and in in the circadian clock within the both of are cardiovascular factors M.E. P. Taegtmeyer H. 2001; PubMed Scopus Google Scholar, M.E. P. P.H. Taegtmeyer H. J. Cardiol. 2002; PubMed Scopus Google Scholar). cardiovascular as and be to the circadian clock within the heart have been to of of peripheral circadian as the pathogenesis of cardiovascular that of the circadian clock within the heart responsiveness of the to fatty A between fatty acid availability and fatty acid rates in accumulation of detrimental fatty acid One way in which a prevents accumulation of detrimental fatty acid in to is through as including cardiomyocytes, the to triglyceride in the of We report that of the circadian clock within the cardiomyocyte induction of β-oxidation triglyceride during fasting. of detrimental fatty acid derivatives is associated with development of myocardial contractile with of 2 and the as insulin resistance, and insulin (15Young M.E. McNulty P.H. Taegtmeyer H. Circulation. 2002; 105: 1861-1870Crossref PubMed Scopus (404) Google Scholar, 16Unger R.H. Orci L. FASEB J. 2001; 15: 312-332Crossref PubMed Scopus (380) Google Scholar, 17Sharma S. Adrogue J.V. Golfman L. Uray I. Lemm J. Youker K. Noon G.P. Frazier O.H. Taegtmeyer H. FASEB J. 2004; 18: 1692-1700Crossref PubMed Scopus (624) Google Scholar, 2002; PubMed Scopus Google Scholar, M. M. R. S. A. PubMed Scopus Google Scholar). If the circadian clock within skeletal and responsiveness of to fatty of this accumulation of detrimental we as for the heart, re-entrainment of the circadian clock within skeletal muscle an as of responsiveness to fatty J. and M. E. is that circadian peripheral to a of environmental in to fatty These diurnal variations in sympathetic (e.g. (e.g. as as blood to respond appropriately to or more of environmental be to to the development of multiple as 2 and cardiovascular the of diurnal variations in the responsiveness of the cardiomyocyte to fatty acids in of the L/D cycle is associated with in the responsiveness of the heart to fatty acids and a loss of synchronization between the circadian clock within the heart and the of re-entrainment of the circadian clock within the heart was to the of in the responsiveness of the heart to fatty responsiveness of the heart to fasting was attenuated of the circadian clock within cardiomyocytes of the heart expose a causal between the responsiveness of the heart to fatty acids and the circadian clock within the in the circadian clock within the cardiomyocyte cardiovascular with