Perm1 promotes cardiomyocyte mitochondrial biogenesis and protects against hypoxia/reoxygenation-induced damage in mice

Abstract

Normal contractile function of the heart depends on a constant and reliable production of ATP by cardiomyocytes. Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. Further, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and estrogen-related receptor (ERR)-induced regulator, muscle 1) that is enriched in skeletal and cardiac-muscle mitochondria and transcriptionally regulated by PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) and ERR. The role of Perm1 in the heart is poorly understood and is studied here. We utilized cell culture, mouse models, and human tissue, to study its expression and transcriptional control, as well as its role in transcription of other factors. Critically, we tested Perm1's role in cardiomyocyte mitochondrial function and its ability to protect myocytes from stress-induced damage. Our studies show that Perm1 expression increases throughout mouse cardiogenesis, demonstrate that Perm1 interacts with PGC-1α and enhances activation of PGC-1 and ERR, increases mitochondrial DNA copy number, and augments oxidative capacity in cultured neonatal mouse cardiomyocytes. Moreover, we found that Perm1 reduced cellular damage produced as a result of hypoxia and reoxygenation-induced stress and mitigated cell death of cardiomyocytes. Taken together, our results show that Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction induced by ischemic injury. Normal contractile function of the heart depends on a constant and reliable production of ATP by cardiomyocytes. Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. Further, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and estrogen-related receptor (ERR)-induced regulator, muscle 1) that is enriched in skeletal and cardiac-muscle mitochondria and transcriptionally regulated by PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) and ERR. The role of Perm1 in the heart is poorly understood and is studied here. We utilized cell culture, mouse models, and human tissue, to study its expression and transcriptional control, as well as its role in transcription of other factors. Critically, we tested Perm1's role in cardiomyocyte mitochondrial function and its ability to protect myocytes from stress-induced damage. Our studies show that Perm1 expression increases throughout mouse cardiogenesis, demonstrate that Perm1 interacts with PGC-1α and enhances activation of PGC-1 and ERR, increases mitochondrial DNA copy number, and augments oxidative capacity in cultured neonatal mouse cardiomyocytes. Moreover, we found that Perm1 reduced cellular damage produced as a result of hypoxia and reoxygenation-induced stress and mitigated cell death of cardiomyocytes. Taken together, our results show that Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction induced by ischemic injury. Proper homeostasis of cellular energy is central to maintain normal heart development and cardiac muscle function (1Stanley W.C. Recchia F.A. Lopaschuk G.D. Myocardial substrate metabolism in the normal and failing heart.Physiol. Rev. 2005; 85: 1093-1129Crossref PubMed Scopus (1395) Google Scholar, 2Taegtmeyer H. Young M.E. Lopaschuk G.D. Abel E.D. Brunengraber H. Darley-Usmar V. Des Rosiers C. Gerszten R. Glatz J.F. Griffin J.L. Gropler R.J. Holzhuetter H.G. Kizer J.R. Lewandowski E.D. Malloy C.R. et al.Assessing cardiac metabolism: A scientific statement from the American Heart Association.Circ. Res. 2016; 118: 1659-1701Crossref PubMed Scopus (150) Google Scholar). Impaired capacity for energy production, as seen in patients with mutations in mitochondrial DNA or nuclear genes encoding lipid oxidation enzymes or respiratory chain components, can lead to cardiac dysfunction (3Wang J. Wilhelmsson H. Graff C. Li H. Oldfors A. Rustin P. Bruning J.C. Kahn C.R. Clayton D.A. Barsh G.S. Thoren P. Larsson N.G. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression.Nat. Genet. 1999; 21: 133-137Crossref PubMed Scopus (332) Google Scholar, 4Park C.B. Larsson N.G. Mitochondrial DNA mutations in disease and aging.J. Cell Biol. 2011; 193: 809-818Crossref PubMed Scopus (206) Google Scholar). An inability to match energy supply to energy needs is also seen in animal models of heart failure (HF) as well as cardiomyopathies in humans (5Vasquez-Trincado C. Garcia-Carvajal I. Pennanen C. Parra V. Hill J.A. Rothermel B.A. Lavandero S. Mitochondrial dynamics, mitophagy and cardiovascular disease.J. Physiol. 2016; 594: 509-525Crossref PubMed Scopus (271) Google Scholar, 6Ventura-Clapier R. Garnier A. Veksler V. Energy metabolism in heart failure.J. Physiol. 2004; 555: 1-13Crossref PubMed Scopus (384) Google Scholar). For instance, cardiac mitochondrial number and activity are downregulated in myocardium in both animal models of HF and HF patients (7Garnier A. Fortin D. Delomenie C. Momken I. Veksler V. Ventura-Clapier R. Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles.J. Physiol. 2003; 551: 491-501Crossref PubMed Scopus (342) Google Scholar, 8Mettauer B. Zoll J. Garnier A. Ventura-Clapier R. Heart failure: A of cardiac and skeletal muscle PubMed Scopus Google Scholar, S. mitochondrial in human PubMed Scopus Google Scholar). A is seen in by or V. Mitochondrial and in for J. Physiol. Heart Physiol. PubMed Scopus Google Scholar). mitochondrial function beneficial effects on HF by and H. D. S. A. H. of mitochondrial transcription a mitochondrial and cardiac failure 2005; PubMed Scopus Google Scholar, Mitochondrial to protect cardiac and Physiol. 2011; PubMed Scopus Google Scholar). the that mitochondrial and function lead to novel therapeutic that can be for the of with cardiac proliferator-activated receptor gamma coactivator and the nuclear estrogen-related receptor central in cardiac metabolism and of cardiac metabolism and mitochondrial Biol. 2011; PubMed Scopus Google Scholar). The expression of factors in cardiac myocytes the in mitochondrial biogenesis and in with the found in S. S. Li and gene is a of the failing human PubMed Scopus Google Scholar). PGC-1α or show in the and PGC-1α HF to stress S. A. to heart failure in coactivator S. A. PubMed Scopus Google Scholar). Further, of both PGC-1α and with heart reduced heart and of HF C. A. and for of the PubMed Scopus Google Scholar). also of HF with cardiac show in the from to oxidation C.R. A. V. The nuclear receptor is for the and to cardiac PubMed Scopus Google Scholar, C.R. V. and the to oxidative metabolism in the PubMed Scopus Google Scholar). and the role of novel that with and is to the of the cardiac both and with Previously, we a novel muscle enriched termed Perm1 (PGC-1 and regulator, muscle 1) A. proliferator-activated receptor gamma coactivator and estrogen-related receptor (ERR)-induced in muscle is a of oxidative capacity in skeletal muscle Biol. PubMed Scopus Google Scholar). Perm1 is in the heart and skeletal and in skeletal is induced by as well as by as A. proliferator-activated receptor gamma coactivator and estrogen-related receptor (ERR)-induced in muscle is a of oxidative capacity in skeletal muscle Biol. PubMed Scopus Google Scholar). cultured skeletal Perm1 is for mitochondrial biogenesis and PGC-1α and gene of Perm1 in skeletal muscle also mitochondrial biogenesis and oxidative capacity S. A. Perm1 enhances mitochondrial oxidative and in adult skeletal J. 2016; PubMed Scopus Google Scholar). of skeletal muscle Perm1 biogenesis S. J.R. B. A. Perm1 activation and skeletal muscle to PubMed Scopus Google Scholar). that Perm1 role in skeletal muscle oxidative We the Perm1 is in the heart and its as well as skeletal its role in and the heart is J. R. A. J. I. et cardiac as a of the PubMed Scopus Google Scholar). we assess its expression in the and we a mouse neonatal cardiomyocyte Our show that Perm1 is a of mitochondrial biogenesis and oxidative capacity in and from cellular damage induced by hypoxia to the role of Perm1 in the we studied Perm1 is in the of mitochondrial function and biogenesis in the Perm1 protein expression in and mitochondrial protein expression development is mitochondrial number and activity to the energy and contractile activity of the heart as to its J. Ventura-Clapier R. of cardiac energy metabolism Physiol. PubMed Scopus Google Scholar). mouse from of cardiogenesis, we cardiac and in the adult heart heart with are of Perm1 the is and the is we have that transcriptional are understood and the Perm1 we also and both and expression seen to to A and to Perm1 protein expression to results show that Perm1 protein expression is from to its as the heart to the role that Perm1 have in the we biogenesis cardiac in DNA seen to in heart as from to adult in with the Perm1 is well that oxidative is a to in ATP show that in protein is by biogenesis J. Ventura-Clapier R. of cardiac energy metabolism Physiol. PubMed Scopus Google Scholar, G.D. Energy of the cardiomyocyte and PubMed Scopus Google Scholar). we protein expression cardiac in and to Perm1 protein and copy number, also cardiac development and protein and as the heart in the adult that our that Perm1 is a of PGC-1 and in skeletal we of and from the and in with the protein expression of the of Perm1 in cardiac as heart from to a Perm1 as with that Perm1 increases in the of PGC-1α cardiac development and and PGC-1α as and expression as PGC-1α a from to in the adult heart its with results that and throughout cardiac development also show that factors expression in the The expression of Perm1 in cardiac as well as its in is Perm1 expression is in disease in and Perm1 protein in mouse and and with from skeletal used as a is to Perm1 on our A. proliferator-activated receptor gamma coactivator and estrogen-related receptor (ERR)-induced in muscle is a of oxidative capacity in skeletal muscle Biol. PubMed Scopus Google Scholar, S. J.R. B. A. Perm1 activation and skeletal muscle to PubMed Scopus Google Scholar). in expression of Perm1 protein as with or we of mouse to study the of Perm1 in that cardiac and nuclear by and used to demonstrate the of in we found Perm1 in with in and A study also that Perm1 protein is in to in S. C. H. P. S. A. Bruning J. et of the heart mitochondrial PubMed Scopus Google Scholar). Perm1 have a is that Perm1 with other leading to its in that Perm1 protein expression is to have a function in of the in humans and show a in oxidative metabolism and dysfunction (7Garnier A. Fortin D. Delomenie C. Momken I. Veksler V. Ventura-Clapier R. Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles.J. Physiol. 2003; 551: 491-501Crossref PubMed Scopus (342) Google Scholar, 8Mettauer B. Zoll J. Garnier A. Ventura-Clapier R. Heart failure: A of cardiac and skeletal muscle PubMed Scopus Google Scholar, S. mitochondrial in human PubMed Scopus Google Scholar, A. S. mitochondrial function in myocardium of with heart failure.J. PubMed Scopus Google Scholar). the expression and activity of cardiac PGC-1α and are downregulated in cardiac from HF patients and animal models of HF S. S. Li and gene is a of the failing human PubMed Scopus Google that the of to the of we Perm1 expression mouse heart from with HF induced by produced by M.E. J. of and expression of in in of cardiac S. A. PubMed Scopus Google Scholar, Li R. S. J. Abel E.D. expression in the heart and the to Biol. PubMed Scopus Google Scholar). cardiac function with cardiac in and Perm1 and protein in with that Perm1 are with cardiac dysfunction. we also protein in from normal human heart as with from from patients with cardiomyopathy Li R. S. J. Abel E.D. expression in the heart and the to Biol. PubMed Scopus Google Scholar, C. Li J. et of in human PubMed Scopus Google Scholar). in protein with normal show that Perm1 is downregulated in cardiac from failing as with in both and are of Perm1 protein and A. proliferator-activated receptor gamma coactivator and estrogen-related receptor (ERR)-induced in muscle is a of oxidative capacity in skeletal muscle Biol. PubMed Scopus Google The protein in to the found to be the our of Perm1 in skeletal muscle and heart A. proliferator-activated receptor gamma coactivator and estrogen-related receptor (ERR)-induced in muscle is a of oxidative capacity in skeletal muscle Biol. PubMed Scopus Google Scholar). of human and mouse Perm1 that both we studied the Perm1 by from with the the and the from the the we and A Perm1 from the of as well as its the in the A to B. function as a We also Perm1 the with the or the The from the and to the of in A to of of as that a Perm1 of of the to in of the the that the Perm1 results from of the of the the results show that from the of in PubMed Scopus Google Scholar, A of the protein S. A. PubMed Scopus Google Scholar, J. of by Res. PubMed Google the of we tested a the of the Perm1 A mutations to the the of of rat in PubMed Scopus Google Perm1 with the or the and both with expression of the of and the of Perm1 results show that the can of a is to the the be to and are and and of and are and the is the protein of and in the results the that and be from other the potential role of Perm1 in and we tested Perm1 biogenesis and oxidative metabolism in neonatal with Perm1 or as we protein expression and DNA copy in A and Perm1 protein expression Perm1 copy number, by expression of genes for by the and and Perm1 genes and to show the effects of the DNA and protein produced by in Perm1 on the of the with the produced by also by Perm1 results that Perm1 enhances biogenesis in the and can result in we to the by Perm1 oxidative metabolism in We genes that are for biogenesis and oxidative function in the as in Perm1 to increases in and Perm1 also expression of the factors and mitochondrial are of mitochondrial transcription factors and by nuclear respiratory factors and and PGC-1 Biol. 2005; PubMed Scopus Google Scholar, A. J.A. J. R. proliferator-activated transcription of the of the Biol. 2011; PubMed Scopus Google Scholar, R. H. a of role in the of and mitochondrial PubMed Scopus Google Scholar, C. J. R. A. J. P. J. R. H. A. et is a novel of cardiac and mitochondrial 2011; PubMed Scopus Google Further, Perm1 expression of other genes to be for as and and energy as and C.R. A. V. The nuclear receptor is for the and to cardiac PubMed Scopus Google Scholar, J. J. M.E. I. Abel E.D. in to or J. Physiol. Heart Physiol. PubMed Scopus Google we in genes for and as protein of and that Perm1 be for metabolism in the to gene we also the of Perm1 on protein expression of and gene expression by in and Perm1 and protein in results that Perm1 by PGC-1 and PGC-1 and to mitochondrial biogenesis and assess potential of Perm1 cellular we a of and on its role as a nuclear human and mouse a nuclear and a nuclear that are A. proliferator-activated receptor gamma coactivator and estrogen-related receptor (ERR)-induced in muscle is a of oxidative capacity in skeletal muscle Biol. PubMed Scopus Google Scholar). other protein are that the Perm1 Perm1 have a nuclear function in we with J. A. the capacity of S. A. PubMed Scopus Google in the or of expression for and are a to the of Perm1 on activity as have activity J. A. the capacity of S. A. PubMed Scopus Google Scholar). in the depends on PGC-1α the activity with Perm1 the Perm1 the activity both in the and in the of with in the of Perm1 a as seen in and Perm1 activity with Perm1 transcriptional activity in the of Perm1 have for ERR. effects of Perm1 found in that activity with of or we that the the on Perm1's ability to we that Perm1 with with PGC-1α Cell to by a by in Perm1 with that Perm1 with the of we the of Perm1 and PGC-1α in the heart tissue, in protein to by by in Perm1 with that Perm1 interacts with PGC-1α in the that Perm1 increases PGC-1 and interacts with and enhances transcriptional we used to Perm1 is on and of PGC-1α to gene is cardiac cell we used cultured skeletal muscle Perm1 genes and biogenesis is to A. proliferator-activated receptor gamma coactivator and estrogen-related receptor (ERR)-induced in muscle is a of oxidative capacity in skeletal muscle Biol. PubMed Scopus Google Scholar). with or Perm1 or with both PGC-1α and Perm1 cell and to normal or DNA to to the of PGC-1α and on gene We studied in the and We to study genes as are by Perm1 of and identified C.R. A. V. The nuclear receptor is for the and to cardiac PubMed Scopus Google Scholar, A. J.A. J. R. proliferator-activated transcription of the of the Biol. 2011; PubMed Scopus Google Scholar). in the of the of PGC-1α on with that PGC-1α is the of and of Perm1 with PGC-1α the of PGC-1α on the with PGC-1α we also found that of Perm1 on the is by of Perm1 with that Perm1 is also the and in of PGC-1α or Perm1 in a that have the in cell to in we adult heart with to assess We the of Perm1 in the a with adult heart and used as in The with and with we a we of or with results that Perm1 is to the in the cardiac leading to in B. Mitochondrial dysfunction and for novel Rev. PubMed Scopus Google Scholar). have that function and number from cell death and cardiac dysfunction induced by H. D. S. A. H. of mitochondrial transcription a mitochondrial and cardiac failure 2005; PubMed Scopus Google Scholar, S. H. D. A. of or increases copy number and with mitochondrial oxidative PubMed Scopus Google Scholar). that Perm1 increases we that Perm1 effects cellular damage by we in of with Perm1 or the to or in damage by of the in the cell in both Perm1 and Perm1 the of cellular damage as by we Perm1 For we of in in and to the number of in with and results that Perm1 from the we have our of Perm1 expression and function in the For we from the and adult mouse we used a neonatal mouse to study Perm1 in normal and of the also we found that Perm1 with cardiac development in mouse expression is to and gene expression of and We also found that Perm1 downregulated in a mouse of heart failure and also in human heart from in to the from we found that Perm1 mitochondrial DNA copy number, and in that Perm1 promotes biogenesis in Moreover, our results that Perm1 for biogenesis and oxidative We also found that Perm1 PGC-1α both in and in heart in transcriptional and of PGC-1α to gene Perm1 as a of biogenesis in PGC-1 in the we found that Perm1 a cellular damage induced by in An in oxidative capacity is a of cardiac and biogenesis a role in the of the heart J. Ventura-Clapier R. of cardiac energy metabolism Physiol. PubMed Scopus Google Scholar). the the oxidative metabolism is poorly in and the on as a of energy J. Ventura-Clapier R. of cardiac energy metabolism Physiol. PubMed Scopus Google Scholar, G.D. Energy of the cardiomyocyte and PubMed Scopus Google Scholar). cardiac development and the oxidative capacity increases and the heart from to oxidative as a of in to energy of the heart J. Ventura-Clapier R. of cardiac energy metabolism Physiol. PubMed Scopus Google Scholar). from a number of studies that of metabolism in of also in cardiac A. V. cardiomyocyte oxidative energy PubMed Scopus Google Scholar, A. in with of PubMed Scopus Google Scholar, J.R. The cardiac mitochondrial and 2011; 21: PubMed Scopus Google Scholar). are studies and are from expression in the heart in in and development of cardiomyopathy C. A. and for of the PubMed Scopus Google Scholar). we found that the of Perm1 protein increases in and throughout cardiac expression with gene expression of and and results the that Perm1 to biogenesis and in with PGC-1 and ERR, cardiac to of oxidative metabolism in cardiac of function is well in the failing heart in and humans B. R. Mitochondrial dysfunction in of heart failure.J. PubMed Scopus Google Scholar, A. A. Clayton D.A. R. Larsson N.G. A in metabolism mitochondrial biogenesis in respiratory mouse S. A. 2004; PubMed Scopus Google Scholar). of the mitochondrial DNA HF A. A. Clayton D.A. R. Larsson N.G. A in metabolism mitochondrial biogenesis in respiratory mouse S. A. 2004; PubMed Scopus Google Scholar). is downregulated in heart from both and ischemic cardiomyopathy with that from normal S. mitochondrial in human PubMed Scopus Google Scholar, G.S. R. DNA mitochondrial biogenesis in human failing Res. PubMed Scopus Google Scholar). of the of normal mitochondrial is in a cardiomyopathy by S. Mitochondrial in PubMed Scopus Google Scholar). with we found that Perm1 expression downregulated in both a mouse heart failure and human heart from patients with as to from normal is that of Perm1 in the failing heart is the of PGC-1 as and are also downregulated in animal models with HF C.R. A. V. The nuclear receptor is for the and to cardiac PubMed Scopus Google results that the of also to dysfunction as seen in HF in humans and the we also that Perm1 the of PGC-1α to gene PGC-1α enhances gene expression with and receptor P. R. A coactivator of nuclear to PubMed Scopus Google and as the protein coactivator S. S. of and function coactivator 2003; PubMed Scopus Google Scholar). that PGC-1α as and D. D. A. of the transcriptional coactivator PGC-1 with a S. A. PubMed Scopus Google Scholar, C. A. P. metabolism transcriptional of PubMed Scopus Google Scholar). our we that Perm1 with and protein and activity in skeletal muscle S. J.R. B. A. Perm1 activation and skeletal muscle to PubMed Scopus Google Scholar). We are that are and have in skeletal muscle as with the heart M.E. in and heart failure.J. 2011; PubMed Scopus Google Scholar). and are in skeletal muscle and are for its contractile and function increases protein activity in human skeletal Physiol. 2003; PubMed Scopus Google is in H. J. The nuclear of protein and cardiomyopathy with protein Biol. PubMed Scopus Google Scholar). studies are to study cardiac activity is by PGC-1α and the of to the for energy for the cardiac mitochondria also a role in the heart by as as can cardiac or in the of that can the heart is to damage to the mitochondrial chain and production of the as a cardiac is or is and of the mitochondrial to of mitochondrial enzymes and from the in cell death B. Mitochondrial dysfunction and for novel Rev. PubMed Scopus Google Scholar). studies that function can effects with reduced production B. J. J. Myocardial oxidative in J. Physiol. PubMed Google Scholar, S. of mitochondria and PubMed Scopus Google Scholar). Perm1 in our neonatal we that Perm1 protect the heart to by of are or in Perm1 that for of its is to that as we et S. C. H. P. S. A. Bruning J. et of the heart mitochondrial PubMed Scopus Google the in the the to studies on identified that Perm1 is in the and the by of its of Perm1 expression lipid and in the mouse we a mitochondrial in the Perm1 is that Perm1 with other leading to its in Our study found that of Perm1 are with The of are be that the of Perm1 a function with the we have identified a in studies that the of the and of the also mutations to the the of of rat in PubMed Scopus Google Scholar). studies the in Perm1 be to is to that Perm1 the protein of we that Perm1 as a protein to the as S. S. of and function coactivator 2003; PubMed Scopus Google Scholar). 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