Publications by authors named "Glenn C Rowe"

48 Publications

Angiotensin II-induced muscle atrophy via PPARγ suppression is mediated by miR-29b.

Mol Ther Nucleic Acids 2021 Mar 25;23:743-756. Epub 2020 Dec 25.

Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China.

The activation of the renin-angiotensin system (RAS) induced by increased angiotensin II (AngII) levels has been implicated in muscle atrophy, which is involved in the pathogenesis of congestive heart failure. Although peroxisome proliferator-activated receptor gamma (PPARγ) activation can suppress RAS, the exact role of PPARγ in AngII-induced muscle atrophy is unclear. Here we identified PPARγ as a negative regulator of miR-29b, a microRNA that is able to promote multiple types of muscle atrophy. Suppression of miR-29b could prevent AngII-induced muscle atrophy both and . IGF1, PI3K(p85α), and Yin Yang 1 (YY1) were identified as target genes of miR-29b, and overexpression of these targets could rescue AngII-induced muscle atrophy. Importantly, inhibition of PPARγ was sufficient to induce muscle atrophy, while PPARγ overexpression could attenuate that. These data indicate that the PPARγ/miR-29b axis mediates AngII-induced muscle atrophy, and increasing PPARγ or inhibiting miR-29b represents a promising approach to counteract AngII-induced muscle atrophy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.omtn.2020.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868689PMC
March 2021

Inhibition of lncRNA MAAT Controls Multiple Types of Muscle Atrophy by cis- and trans-Regulatory Actions.

Mol Ther 2021 Mar 3;29(3):1102-1119. Epub 2020 Dec 3.

Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Sciences, Shanghai University, Shanghai 200444, China; School of Medicine, Shanghai University, Shanghai 200444, China. Electronic address:

Muscle atrophy is associated with negative outcomes in a variety of diseases. Identification of a common therapeutic target would address a significant unmet clinical need. Here, we identify a long non-coding RNA (lncRNA) (muscle-atrophy-associated transcript, lncMAAT) as a common regulator of skeletal muscle atrophy. lncMAAT is downregulated in multiple types of muscle-atrophy models both in vivo (denervation, Angiotensin II [AngII], fasting, immobilization, and aging-induced muscle atrophy) and in vitro (AngII, HO, and tumor necrosis factor alpha [TNF-α]-induced muscle atrophy). Gain- and loss-of-function analysis both in vitro and in vivo reveals that downregulation of lncMAAT is sufficient to induce muscle atrophy, while overexpression of lncMAAT can ameliorate multiple types of muscle atrophy. Mechanistically, lncMAAT negatively regulates the transcription of miR-29b through SOX6 by a trans-regulatory module and increases the expression of the neighboring gene Mbnl1 by a cis-regulatory module. Therefore, overexpression of lncMAAT may represent a promising therapy for muscle atrophy induced by different stimuli.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymthe.2020.12.002DOI Listing
March 2021

PRDM16 suppresses HIF-targeted gene expression in kidney cancer.

J Exp Med 2020 06;217(6)

Department of Urology, University of Alabama at Birmingham, Birmingham, AL.

Analysis of transcriptomic data demonstrates extensive epigenetic gene silencing of the transcription factor PRDM16 in renal cancer. We show that restoration of PRDM16 in RCC cells suppresses in vivo tumor growth. RNaseq analysis reveals that PRDM16 imparts a predominantly repressive effect on the RCC transcriptome including suppression of the gene encoding semaphorin 5B (SEMA5B). SEMA5B is a HIF target gene highly expressed in RCC that promotes in vivo tumor growth. Functional studies demonstrate that PRDM16's repressive properties, mediated by physical interaction with the transcriptional corepressors C-terminal binding proteins (CtBP1/2), are required for suppression of both SEMA5B expression and in vivo tumor growth. Finally, we show that reconstitution of RCC cells with a PRDM16 mutant unable to bind CtBPs nullifies PRDM16's effects on both SEMA5B repression and tumor growth suppression. Collectively, our data uncover a novel epigenetic basis by which HIF target gene expression is amplified in kidney cancer and a new mechanism by which PRDM16 exerts its tumor suppressive effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20191005DOI Listing
June 2020

Effects of on Microglial-Derived Extracellular Vesicle Biogenesis and Composition.

Pathogens 2019 Dec 14;8(4). Epub 2019 Dec 14.

Microbiology Program, Department of Biological Sciences, College of Science, Technology, Engineering and Mathematics, Alabama State University, Montgomery, AL 36104, USA.

The packaging of molecular constituents inside extracellular vesicles (EVs) allows them to participate in intercellular communication and the transfer of biological molecules, however the role of EVs during bacterial infection is poorly understood. The goal of this study was to examine the effects of ( infection on the biogenesis and composition of EVs derived from the mouse microglia cell line, BV-2. BV-2 cells were cultured in exosome-free media and infected with 0, 1.3 × 10, or 2.6 × 10 colony forming units per milliliter for 72 h. The results indicated that compared with the control group, BV-2 cell viability significantly decreased after infection and BV-2-derived EVs concentration decreased significantly in the infected group. infection significantly decreased chemokine ligand 4 messenger RNA in BV-2-derived infected EVs, compared with the control group ( ≤ 0.05). This study also revealed that heat shock protein 70 ( ≤ 0.05) and heat shock protein 90β ( ≤ 0.001) levels of expression within EVs increased after infection. EV treatment with EVs derived from infection reduced cell viability of BV-2 cells. infection alters the expression of specific proteins and mRNA in EVs. Our study suggests that infection modulates EV biogenesis and composition, which may influence bacterial pathogenesis and infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pathogens8040297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963293PMC
December 2019

Genetic Deletion of Alters Body Composition, Metabolic Phenotypes, and the Function of Metabolic Tissues in Female Mice Fed A High-Fat Diet.

Nutrients 2019 Nov 18;11(11). Epub 2019 Nov 18.

Department of Surgery, Ohio State University, Columbus, OH 43209, USA.

Syndecans are transmembrane proteoglycans that, like integrins, bind to components of the extracellular matrix. Previously, we showed significant associations of genetic variants in the () gene with intra-abdominal fat, fasting plasma glucose levels, and insulin sensitivity index in children, and with fasting serum triglyceride levels in healthy elderly subjects. An independent study also reported a correlation between and the risk of coronary artery disease in middle-aged patients. Here, we investigated whether deletion of promotes metabolic derangements associated with diet-induced obesity by feeding homozygous male and female -deficient () mice and their age-matched wild-type (WT) mice a high-fat diet (HFD). We found that WT and mice gained similar weight. However, while no differences were observed in males, HFD-fed female mice exhibited a higher percentage of body fat mass than controls and displayed increased levels of plasma total cholesterol, triglyceride, and glucose, as well as reduced whole-body insulin sensitivity. Additionally, they had an increased adipocyte size and macrophage infiltration in the visceral adipose tissue, and higher triglyceride and fatty acid synthase levels in the liver. Together with our previous human genetic findings, these results provide evidence of an evolutionarily conserved role of in adiposity and its complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu11112810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893658PMC
November 2019

The Role of Lipopolysaccharide-Induced Extracellular Vesicles in Cardiac Cell Death.

Biology (Basel) 2019 Sep 23;8(4). Epub 2019 Sep 23.

Microbiology Program, Department of Biological Sciences, College of Science, Technology, Engineering and Mathematics, Alabama State University, Montgomery, AL 36104, USA.

Exosomes play a crucial role in the progression of infectious diseases, as exosome release and biogenesis are affected by external factors, such as pathogenic infections. Pyrogens may aide in the progression of diseases by triggering inflammation, endothelial cell injury, and arterial plaque rupture, all of which can lead to acute coronary disease, resulting in cardiac tissue death and the onset of a cardiac event (CE). To better understand the effects of Gram-negative bacterial infections on exosome composition and biogenesis, we examined exosome characteristics after treatment of AC16 human cardiomyocytes with lipopolysaccharide (LPS), which served as a model system for Gram-negative bacterial infection. Using increasing doses (0, 0.1, 1, or 10 µg) of LPS, we showed that treatment with LPS substantially altered the composition of AC16-derived exosomes. Both the relative size and the quantity (particles/mL) of exosomes were decreased significantly at all tested concentrations of LPS treatment compared to the untreated group. In addition, LPS administration reduced the expression of exosomal proteins that are related to exosomal biogenesis. Conversely, we observed an increase in immunomodulators present after LPS administration. This evaluation of the impact of LPS on cardiac cell death and exosome composition will yield new insight into the importance of exosomes in a variety of physiological and pathological processes as it relates to disease progression, diagnosis, and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biology8040069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955717PMC
September 2019

HDAC inhibition induces autophagy and mitochondrial biogenesis to maintain mitochondrial homeostasis during cardiac ischemia/reperfusion injury.

J Mol Cell Cardiol 2019 05 14;130:36-48. Epub 2019 Mar 14.

Dept. of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America. Electronic address:

Aims: The FDA-approved histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA, Vorinostat) has been shown to induce cardiomyocyte autophagy and blunt ischemia/reperfusion (I/R) injury when administered at the time of reperfusion. However, the precise mechanisms underlying the cardioprotective activity of SAHA are unknown. Mitochondrial dysfunction and oxidative damage are major contributors to myocardial apoptosis during I/R injury. We hypothesize that SAHA protects the myocardium by maintaining mitochondrial homeostasis and reducing reactive oxygen species (ROS) production during I/R injury.

Methods: Mouse and cultured cardiomyocytes (neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes) I/R models were used to investigate the effects of SAHA on mitochondria. ATG7 knockout mice, ATG7 knockdown by siRNA and PGC-1α knockdown by adenovirus in cardiomyocytes were used to test the dependency of autophagy and PGC-1α-mediated mitochondrial biogenesis respectively.

Results: Intact and total mitochondrial DNA (mtDNA) content and mitochondrial mass were significantly increased in cardiomyocytes by SAHA pretreatment before simulated I/R. In vivo, I/R induced >50% loss of mtDNA content in the border zones of mouse hearts, but SAHA pretreatment and reperfusion treatment alone reverted mtDNA content and mitochondrial mass to control levels. Moreover, pretreatment of cardiomyocytes with SAHA resulted in a 4-fold decrease in I/R-induced loss of mitochondrial membrane potential and a 25%-40% reduction in cytosolic ROS levels. However, loss-of-function of ATG7 in cardiomyocytes or mouse myocardium abolished the protective effects of SAHA on ROS levels, mitochondrial membrane potential, mtDNA levels, and mitochondrial mass. Lastly, PGC-1α gene expression was induced by SAHA in NRVMs and mouse heart subjected to I/R, and loss of PGC-1α abrogated SAHA's mitochondrial protective effects in cardiomyocytes.

Conclusions: SAHA prevents I/R induced-mitochondrial dysfunction and loss, and reduces myocardial ROS production when given before or after the ischemia. The protective effects of SAHA on mitochondria are dependent on autophagy and PGC-1α-mediated mitochondrial biogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2019.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502701PMC
May 2019

Age- and Genotype-Specific Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Mitochondrial and Metabolic Parameters in .

Int J Mol Sci 2018 Oct 26;19(11). Epub 2018 Oct 26.

Departments of Nutrition Science, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS) that improve mitochondrial function. Yet, our understanding of the relationship between ACEi therapy and metabolic parameters is limited. Here, we used three genetically diverse strains of to show that Lisinopril treatment reduces thoracic ROS levels and mitochondrial respiration in young flies, and increases mitochondrial content in middle-aged flies. Using untargeted metabolomics analysis, we also showed that Lisinopril perturbs the thoracic metabolic network structure by affecting metabolic pathways involved in glycogen degradation, glycolysis, and mevalonate metabolism. The Lisinopril-induced effects on mitochondrial and metabolic parameters, however, are genotype-specific and likely reflect the drug's impact on nutrient-dependent fitness traits. Accordingly, we found that Lisinopril negatively affects survival under nutrient starvation, an effect that can be blunted by genotype and age in a manner that partially mirrors the drug-induced changes in mitochondrial respiration. In conclusion, our results provide novel and important insights into the role of ACEi in cellular metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms19113351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274988PMC
October 2018

Adult skeletal muscle deletion of Mitofusin 1 and 2 impedes exercise performance and training capacity.

J Appl Physiol (1985) 2019 02 27;126(2):341-353. Epub 2018 Sep 27.

Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Alabama.

Endurance exercise has been shown to be a positive regulator of skeletal muscle metabolic function. Changes in mitochondrial dynamics (fusion and fission) have been shown to influence mitochondrial oxidative capacity. We therefore tested whether genetic disruption of mitofusins (Mfns) affected exercise performance in adult skeletal muscle. We generated adult-inducible skeletal muscle-specific Mfn1 (iMS-Mfn1KO), Mfn2 (iMS-Mfn2KO), and Mfn1/2 (iMS-MfnDKO) knockout mice. We assessed exercise capacity by performing a treadmill time to exhaustion stress test before deletion and up to 8 wk after deletion. Analysis of either the iMS-Mfn1KO or the iMS-Mfn2KO did not reveal an effect on exercise capacity. However, analysis of iMS-MfnDKO animals revealed a progressive reduction in exercise performance. We measured individual electron transport chain (ETC) complex activity and observed a reduction in ETC activity in both the subsarcolemmal and intermyofibrillar mitochondrial fractions specifically for NADH dehydrogenase (complex I) and cytochrome- c oxidase (complex IV), which was associated with a decrease in ETC subunit expression for these complexes. We also tested whether voluntary exercise training would prevent the decrease in exercise capacity observed in iMS-MfnDKO animals ( n = 10/group). However, after 8 wk of training we did not observe any improvement in exercise capacity or ETC subunit parameters in iMS-MfnDKO animals. These data suggest that the decrease in exercise capacity observed in the iMS-MfnDKO animals is in part the result of impaired ETC subunit expression and ETC complex activity. Taken together, these results provide strong evidence that mitochondrial fusion in adult skeletal muscle is important for exercise performance. NEW & NOTEWORTHY This study is the first to utilize an adult-inducible skeletal muscle-specific knockout model for Mitofusin (Mfn)1 and Mfn2 to assess exercise capacity. Our findings reveal a progressive decrease in exercise performance with Mfn1 and Mfn2 deletion. The decrease in exercise capacity was accompanied by impaired oxidative phosphorylation specifically for complex I and complex IV. Furthermore, voluntary exercise training was unable to rescue the impairment, suggesting that normal fusion is essential for exercise-induced mitochondrial adaptations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/japplphysiol.00719.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397407PMC
February 2019

Cell-Specific Deletion of PGC-1α from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment.

J Neurosci 2018 03 28;38(13):3273-3286. Epub 2018 Feb 28.

Department of Neuroscience, Southern Research, Birmingham, Alabama, 35205, and Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, AL 35294,

Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is associated with neurodegeneration in diseases such as Huntington's disease (D). Polymorphisms in the PGC-1α gene modify HD progression and PGC-1α expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-1α nor the contribution of PGC-1α deficiency to motor dysfunction is known. We identified novel, PGC-1α-dependent transcripts involved in RNA processing, signal transduction, and neuronal morphology and confirmed reductions in these transcripts in male and female mice lacking PGC-1α specifically in MSNs, indicating a cell-autonomous effect in this population. MSN-specific PGC-1α deletion caused reductions in previously identified neuronal and metabolic PGC-1α-dependent genes without causing striatal vacuolizations. Interestingly, these mice exhibited a hypoactivity with age, similar to several HD animal models. However, these newly identified PGC-1α-dependent genes were upregulated with disease severity and age in knock-in HD mouse models independent of changes in PGC-1α transcript, contrary to what would be predicted from a loss-of-function etiological mechanism. These data indicate that PGC-1α is necessary for MSN transcriptional homeostasis and function with age and that, whereas PGC-1α loss in MSNs does not replicate an HD-like phenocopy, its downstream genes are altered in a repeat-length and age-dependent fashion. Understanding the additive effects of PGC-1α gene functional variation and mutant huntingtin on transcription in this cell type may provide insight into the selective vulnerability of MSNs in HD. Reductions in peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-mediated transcription have been implicated in the pathogenesis of Huntington's disease (D). We show that, although PGC-1α-dependent transcription is necessary to maintain medium spiny neuron (MSN) function with age, its loss is insufficient to cause striatal atrophy in mice. We also highlight a set of genes that can serve as proxies for PGC-1α functional activity in the striatum for target engagement studies. Furthermore, we demonstrate that PGC-1α-dependent genes are upregulated in a dose- and age-dependent fashion in HD mouse models, contrary to what would be predicted from a loss-of-function etiological mechanism. However, given this role for PGC-1α in MSN transcriptional homeostasis, it is important to consider how genetic variation in PGC-1α could contribute to mutant-huntingtin-induced cell death and disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0848-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884461PMC
March 2018

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy.

Circ Res 2017 Dec 19;121(12):1370-1378. Epub 2017 Sep 19.

From the Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA (L.X.L., F.D.); Corrigan Minehan Heart Center, Massachusetts General Hospital, Boston (L.X.L., F.D., M.C.C., S.D., A.R.); Division of Cardiovascular Disease, University of Alabama at Birmingham (G.C.R.); Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.Y., J.L., S.W., M.M., Z.A.); Lewis-Sigler Institute for Integrative Genomics, Princeton University, NJ (W.L., C.J., J.D.R.); and Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Germany (M.H., B.K.F.).

Rationale: Pregnancy profoundly alters maternal physiology. The heart hypertrophies during pregnancy, but its metabolic adaptations, are not well understood.

Objective: To determine the mechanisms underlying cardiac substrate use during pregnancy.

Methods And Results: We use here C glucose, C lactate, and C fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic acid cycle, while reducing glucose and lactate oxidation. Mitochondrial quantity, morphology, and function do not seem altered. Insulin signaling seems intact, and the abundance and localization of the major fatty acid and glucose transporters, CD36 (cluster of differentiation 36) and GLUT4 (glucose transporter type 4), are also unchanged. Rather, we find that the pregnancy hormone progesterone induces PDK4 (pyruvate dehydrogenase kinase 4) in cardiomyocytes and that elevated PDK4 levels in late pregnancy lead to inhibition of PDH (pyruvate dehydrogenase) and pyruvate flux into the tricarboxylic acid cycle. Blocking PDK4 reverses the metabolic changes seen in hearts in late pregnancy.

Conclusions: Taken together, these data indicate that the hormonal environment of late pregnancy promotes metabolic remodeling in the heart at the level of PDH, rather than at the level of insulin signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.117.311456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722682PMC
December 2017

Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart.

J Mol Cell Cardiol 2017 09 20;110:80-95. Epub 2017 Jul 20.

Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Cardiovascular physiology exhibits time-of-day-dependent oscillations, which are mediated by both extrinsic (e.g., environment/behavior) and intrinsic (e.g., circadian clock) factors. Disruption of circadian rhythms negatively affects multiple cardiometabolic parameters. Recent studies suggest that the cardiomyocyte circadian clock directly modulates responsiveness of the heart to metabolic stimuli (e.g., fatty acids) and stresses (e.g., ischemia/reperfusion). The aim of this study was to determine whether genetic disruption of the cardiomyocyte circadian clock impacts insulin-regulated pathways in the heart. Genetic disruption of the circadian clock in cardiomyocyte-specific Bmal1 knockout (CBK) and cardiomyocyte-specific Clock mutant (CCM) mice altered expression (gene and protein) of multiple insulin signaling components in the heart, including p85α and Akt. Both baseline and insulin-mediated Akt activation was augmented in CBK and CCM hearts (relative to littermate controls). However, insulin-mediated glucose utilization (both oxidative and non-oxidative) and AS160 phosphorylation were attenuated in CBK hearts, potentially secondary to decreased Inhibitor-1. Consistent with increased Akt activation in CBK hearts, mTOR signaling was persistently increased, which was associated with attenuation of autophagy, augmented rates of protein synthesis, and hypertrophy. Importantly, pharmacological inhibition of mTOR (rapamycin; 10days) normalized cardiac size in CBK mice. These data suggest that disruption of cardiomyocyte circadian clock differentially influences insulin-regulated processes, and provide new insights into potential pathologic mediators following circadian disruption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2017.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586500PMC
September 2017

miR-29b contributes to multiple types of muscle atrophy.

Nat Commun 2017 05 25;8:15201. Epub 2017 May 25.

Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai 200444, China.

A number of microRNAs (miRNAs, miRs) have been shown to play a role in skeletal muscle atrophy, but their role is not completely understood. Here we show that miR-29b promotes skeletal muscle atrophy in response to different atrophic stimuli in cells and in mouse models. miR-29b promotes atrophy of myotubes differentiated from C2C12 or primary myoblasts, and conversely, its inhibition attenuates atrophy induced by dexamethasone (Dex), TNF-α and HO treatment. Targeting of IGF-1 and PI3K(p85α) by miR-29b is required for induction of muscle atrophy. In vivo, miR-29b overexpression is sufficient to promote muscle atrophy while inhibition of miR-29b attenuates atrophy induced by denervation and immobilization. These data suggest that miR-29b contributes to multiple types of muscle atrophy via targeting of IGF-1 and PI3K(p85α), and that suppression of miR-29b may represent a therapeutic approach for muscle atrophy induced by different stimuli.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms15201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458521PMC
May 2017

VEGF-B: friend or foe to the heart in times of nutrient excess?

Am J Physiol Heart Circ Physiol 2017 08 19;313(2):H244-H247. Epub 2017 May 19.

Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00158.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582917PMC
August 2017

Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function.

PLoS One 2017 3;12(2):e0170458. Epub 2017 Feb 3.

Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America.

Mitochondrial dysfunction contributes to myriad monogenic and complex pathologies. To understand the underlying mechanisms, it is essential to define the full complement of proteins that modulate mitochondrial function. To identify such proteins, we performed a meta-analysis of publicly available gene expression data. Gene co-expression analysis of a large and heterogeneous compendium of microarray data nominated a sub-population of transcripts that whilst highly correlated with known mitochondrial protein-encoding transcripts (MPETs), are not themselves recognized as generating proteins either localized to the mitochondrion or pertinent to functions therein. To focus the analysis on a medically-important condition with a strong yet incompletely understood mitochondrial component, candidates were cross-referenced with an MPET-enriched module independently generated via genome-wide co-expression network analysis of a human heart failure gene expression dataset. The strongest uncharacterized candidate in the analysis was Leucine Rich Repeat Containing 2 (LRRC2). LRRC2 was found to be localized to the mitochondria in human cells and transcriptionally-regulated by the mitochondrial master regulator Pgc-1α. We report that Lrrc2 transcript abundance correlates with that of β-MHC, a canonical marker of cardiac hypertrophy in humans and experimentally demonstrated an elevation in Lrrc2 transcript in in vitro and in vivo rodent models of cardiac hypertrophy as well as in patients with dilated cardiomyopathy. RNAi-mediated Lrrc2 knockdown in a rat-derived cardiomyocyte cell line resulted in enhanced expression of canonical hypertrophic biomarkers as well as increased mitochondrial mass in the context of increased Pgc-1α expression. In conclusion, our meta-analysis represents a simple yet powerful springboard for the nomination of putative mitochondrially-pertinent proteins relevant to cardiac function and enabled the identification of LRRC2 as a novel mitochondrially-relevant protein and regulator of the hypertrophic response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170458PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291451PMC
August 2017

Development of dilated cardiomyopathy and impaired calcium homeostasis with cardiac-specific deletion of ESRRβ.

Am J Physiol Heart Circ Physiol 2017 Apr 27;312(4):H662-H671. Epub 2017 Jan 27.

Cardiovascular Institute, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts.

Mechanisms underlying the development of idiopathic dilated cardiomyopathy (DCM) remain poorly understood. Using transcription factor expression profiling, we identified estrogen-related receptor-β (ESRRβ), a member of the nuclear receptor family of transcription factors, as highly expressed in murine hearts and other highly oxidative striated muscle beds. Mice bearing cardiac-specific deletion of ESRRβ (MHC-ERRB KO) develop DCM and sudden death at ~10 mo of age. Isolated adult cardiomyocytes from the MHC-ERRB KO mice showed an increase in calcium sensitivity and impaired cardiomyocyte contractility, which preceded echocardiographic cardiac remodeling and dysfunction by several months. Histological analyses of myocardial biopsies from patients with various cardiomyopathies revealed that ESRRβ protein is absent from the nucleus of cardiomyocytes from patients with DCM but not other forms of cardiomyopathy (ischemic, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy). Taken together these observations suggest that ESRRβ is a critical component in the onset of DCM by affecting contractility and calcium balance. Estrogen-related receptor-β (ESRRβ) is highly expressed in the heart and cardiac-specific deletion results in the development of a dilated cardiomyopathy (DCM). ESRRβ is mislocalized in human myocardium samples with DCM, suggesting a possible role for ESRRβ in the pathogenesis of DCM in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00446.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407163PMC
April 2017

Hypothalamic ΔFosB prevents age-related metabolic decline and functions via SNS.

Aging (Albany NY) 2017 01;9(2):353-369

Department of Medicine, Harvard Medical School and Endocrine Unit MGH, and Division of Bone and Mineral Metabolism, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.

The ventral hypothalamus (VHT) integrates several physiological cues to maintain glucose homeostasis and energy balance. Aging is associated with increased glucose intolerance but the underlying mechanisms responsible for age-related metabolic decline, including neuronal signaling in the VHT, remain elusive. We have shown that mice with VHT-targeted overexpression of ∆FosB, a splice variant of the AP1 transcription factor FosB, exhibit increased energy expenditure, leading to decreased adiposity. Here, we show that VHT-targeted overexpression of ∆FosB also improves glucose tolerance, increases insulin sensitivity in target organs and thereby suppresses insulin secretion. These effects are also observed by the overexpression of dominant negative JunD, demonstrating that they occur via AP1 antagonism within the VHT. Furthermore, the improved glucose tolerance and insulin sensitivity persisted in aged animals overexpressing ∆FosB in the VHT. These beneficial effects on glucose metabolism were abolished by peripheral sympathectomy and α-adrenergic, but not β-adrenergic, blockade. Taken together, our results show that antagonizing AP1 transcription activity in the VHT leads to a marked improvement in whole body glucose homeostasis via activation of the SNS, conferring protection against age-related impairment in glucose metabolism. These findings may open novel avenues for therapeutic intervention in diabetes and age-related glucose intolerance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.101157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361668PMC
January 2017

LDB1 Regulates Energy Homeostasis During Diet-Induced Obesity.

Endocrinology 2017 05;158(5):1289-1297

Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism.

The broadly expressed transcriptional coregulator LDB1 is essential for β-cell development and glucose homeostasis. However, it is unclear whether LDB1 has metabolic roles beyond the β-cell, especially under metabolic stress. Global Ldb1 deletion results in early embryonic lethality; thus, we used global heterozygous Ldb1+/- and inducible β-cell-specific Ldb1-deficient (Ldb1Δβ-cell) mice. We assessed glucose and insulin tolerance, body composition, feeding, and energy expenditure during high-fat diet exposure. Brown adipose tissue (BAT) biology was evaluated by thermogenic gene expression and LDB1 chromatin immunoprecipitation analysis. We found that partial loss of Ldb1 does not impair the maintenance of glucose homeostasis; rather, we observed improved insulin sensitivity in these mice. Partial loss of Ldb1 also uncovered defects in energy expenditure in lean and diet-induced obese (DIO) mice. This decreased energy expenditure during DIO was associated with significantly altered BAT gene expression, specifically Cidea, Elovl3, Cox7a1, and Dio2. Remarkably, the observed changes in energy balance during DIO were absent in Ldb1Δβ-cell mice, despite a similar reduction in plasma insulin, suggesting a role for LDB1 in BAT. Indeed, LDB1 is expressed in brown adipocytes and occupies a regulatory domain of Elovl3, a gene crucial to normal BAT function. We conclude that LDB1 regulates energy homeostasis, in part through transcriptional modulation of critical regulators in BAT function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/en.2016-1791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460834PMC
May 2017

The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue.

Genes Dev 2016 11 2;30(22):2551-2564. Epub 2016 Dec 2.

Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth factor and tuberous sclerosis complex (TSC) signaling, is driven by RagC/D, and is separable from canonical mTOR signaling to S6K. Codeletion of TFE3 in adipose-specific FLCN knockout animals rescues adipose tissue browning, as does codeletion of PGC-1β. Conversely, inducible expression of PGC-1β in white adipose tissue is sufficient to induce beige fat gene expression in vivo. These data thus unveil a novel FLCN-mTOR-TFE3-PGC-1β pathway-separate from the canonical TSC-mTOR-S6K pathway-that regulates browning of adipose tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gad.287953.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159669PMC
November 2016

Heme oxygenase and carbon monoxide protect from muscle dystrophy.

Skelet Muscle 2016 11 28;6(1):41. Epub 2016 Nov 28.

Cardiovascular Institute and Institute Diabetes Obesity and Metabolism, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, 11th floor, 3400 Civic Blvd, Philadelphia, 19104, PA, USA.

Background: Duchenne muscle dystrophy (DMD) is one of the most common lethal genetic diseases of children worldwide and is 100% fatal. Steroids, the only therapy currently available, are marred by poor efficacy and a high side-effect profile. New therapeutic approaches are urgently needed.

Methods: Here, we leverage PGC-1α, a powerful transcriptional coactivator known to protect against dystrophy in the mdx murine model of DMD, to search for novel mechanisms of protection against dystrophy.

Results: We identify heme oxygenase-1 (HO-1) as a potential novel target for the treatment of DMD. Expression of HO-1 is blunted in the muscles from the mdx murine model of DMD, and further reduction of HO-1 by genetic haploinsufficiency worsens muscle damage in mdx mice. Conversely, induction of HO-1 pharmacologically protects against muscle damage. Mechanistically, HO-1 degrades heme into biliverdin, releasing in the process ferrous iron and carbon monoxide (CO). We show that exposure to a safe low dose of CO protects against muscle damage in mdx mice, as does pharmacological treatment with CO-releasing molecules.

Conclusions: These data identify HO-1 and CO as novel therapeutic agents for the treatment of DMD. Safety profiles and clinical testing of inhaled CO already exist, underscoring the translational potential of these observations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13395-016-0114-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126804PMC
November 2016

Adult expression of PGC-1α and -1β in skeletal muscle is not required for endurance exercise-induced enhancement of exercise capacity.

Am J Physiol Endocrinol Metab 2016 12 25;311(6):E928-E938. Epub 2016 Oct 25.

Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and

Exercise has been shown to be the best intervention in the treatment of many diseases. Many of the benefits of exercise are mediated by adaptions induced in skeletal muscle. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators has emerged as being key mediators of the exercise response and is considered to be essential for many of the adaptions seen in skeletal muscle. However, the contribution of the PGC-1s in skeletal muscle has been evaluated by the use of either whole body or congenital skeletal muscle-specific deletion. In these models, PGC-1s were never present, thereby opening the possibility to developmental compensation. Therefore, we generated an inducible muscle-specific deletion of PGC-1α and -1β (iMyo-PGC-1DKO), in which both PGC-1α and -β can be deleted specifically in adult skeletal muscle. These iMyo-PGC-1DKO animals were used to assess the role of both PGC-1α and -1β in adult skeletal muscle and their contribution to the exercise training response. Untrained iMyo-PGC-1DKO animals exhibited a time-dependent decrease in exercise performance 8 wk postdeletion, similar to what was observed in the congenital muscle-specific PGC-1DKOs. However, after 4 wk of voluntary training, the iMyo-PGC-1DKOs exhibited an increase in exercise performance with a similar adaptive response compared with control animals. This increase was associated with an increase in electron transport complex (ETC) expression and activity in the absence of PGC-1α and -1β expression. Taken together these data suggest that PGC-1α and -1β expression are not required for training-induced exercise performance, highlighting the contribution of PGC-1-independent mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpendo.00209.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5183883PMC
December 2016

The TreadWheel: A Novel Apparatus to Measure Genetic Variation in Response to Gently Induced Exercise for Drosophila.

PLoS One 2016 13;11(10):e0164706. Epub 2016 Oct 13.

Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, United States of America.

Obesity is one of the dramatic health issues affecting developed and developing nations, and exercise is a well-established intervention strategy. While exercise-by-genotype interactions have been shown in humans, overall little is known. Using the natural negative geotaxis of Drosophila melanogaster, an important model organism for the study of genetic interactions, a novel exercise machine, the TreadWheel, can be used to shed light on this interaction. The mechanism for inducing exercise with the TreadWheel is inherently gentle, thus minimizing possible confounding effects of other stressors. Using this machine, we were able to assess large cohorts of adult flies from eight genetic lines for their response to exercise after one week of training. We measured their triglyceride, glycerol, protein, glycogen, glucose content, and body weight, as well as their climbing ability and feeding behavior in response to exercise. Exercised flies showed decreased stored triglycerides, glycogen, and body weight, and increased stored protein and climbing ability. In addition to demonstrating an overall effect of TreadWheel exercise on flies, we found significant interactions of exercise with genotype, sex, or genotype-by-sex effects for most of the measured phenotypes. We also observed interaction effects between exercise, genotype, and tissue (abdomen or thorax) for metabolite profiles, and those differences can be partially linked to innate differences in the flies' persistence in maintaining activity during exercise bouts. In addition, we assessed gene expression levels for a panel of 13 genes known to be associated with respiratory fitness and found that many responded to exercise. With this study, we have established the TreadWheel as a useful tool to study the effect of exercise in flies, shown significant genotype-specific and sex-specific impacts of exercise, and have laid the ground work for more extensive studies of how genetics, sex, environment, and aging interact with exercise to influence metabolic fitness in Drosophila.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164706PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063428PMC
May 2017

Biotinylation: a novel posttranslational modification linking cell autonomous circadian clocks with metabolism.

Am J Physiol Heart Circ Physiol 2016 06 15;310(11):H1520-32. Epub 2016 Apr 15.

Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;

Circadian clocks are critical modulators of metabolism. However, mechanistic links between cell autonomous clocks and metabolic processes remain largely unknown. Here, we report that expression of the biotin transporter slc5a6 gene is decreased in hearts of two distinct genetic mouse models of cardiomyocyte-specific circadian clock disruption [i.e., cardiomyocyte-specific CLOCK mutant (CCM) and cardiomyocyte-specific BMAL1 knockout (CBK) mice]. Biotinylation is an obligate posttranslational modification for five mammalian carboxylases: acetyl-CoA carboxylase α (ACCα), ACCβ, pyruvate carboxylase (PC), methylcrotonyl-CoA carboxylase (MCC), and propionyl-CoA carboxylase (PCC). We therefore hypothesized that the cardiomyocyte circadian clock impacts metabolism through biotinylation. Consistent with decreased slc5a6 expression, biotinylation of all carboxylases is significantly decreased (10-46%) in CCM and CBK hearts. In association with decreased biotinylated ACC, oleate oxidation rates are increased in both CCM and CBK hearts. Consistent with decreased biotinylated MCC, leucine oxidation rates are significantly decreased in both CCM and CBK hearts, whereas rates of protein synthesis are increased. Importantly, feeding CBK mice with a biotin-enriched diet for 6 wk normalized myocardial 1) ACC biotinylation and oleate oxidation rates; 2) PCC/MCC biotinylation (and partially restored leucine oxidation rates); and 3) net protein synthesis rates. Furthermore, data suggest that the RRAGD/mTOR/4E-BP1 signaling axis is chronically activated in CBK and CCM hearts. Finally we report that the hepatocyte circadian clock also regulates both slc5a6 expression and protein biotinylation in the liver. Collectively, these findings suggest that biotinylation is a novel mechanism by which cell autonomous circadian clocks influence metabolic pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00959.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935513PMC
June 2016

PGC-1α Induces Human RPE Oxidative Metabolism and Antioxidant Capacity.

Invest Ophthalmol Vis Sci 2016 Mar;57(3):1038-51

Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States 2Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.

Purpose: Oxidative stress and metabolic dysregulation of the RPE have been implicated in AMD; however, the molecular regulation of RPE metabolism remains unclear. The transcriptional coactivator, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) is a powerful mediator of mitochondrial function. This study examines the ability of PGC-1α to regulate RPE metabolic program and oxidative stress response.

Methods: Primary human fetal RPE (hfRPE) and ARPE-19 were matured in vitro using standard culture conditions. Mitochondrial mass of RPE was measured using MitoTracker staining and citrate synthase activity. Expression of PGC-1 isoforms, RPE-specific genes, oxidative metabolism proteins, and antioxidant enzymes was analyzed by quantitative PCR and Western blot. Mitochondrial respiration and fatty-acid oxidation were monitored using the Seahorse extracellular flux analyzer. Expression of PGC-1α was increased using adenoviral delivery. ARPE-19 were exposed to hydrogen peroxide to induce oxidative stress. Reactive oxygen species were measured by CM-H2DCFDA fluorescence. Cell death was analyzed by LDH release.

Results: Maturation of ARPE-19 and hfRPE was associated with significant increase in mitochondrial mass, expression of oxidative phosphorylation (OXPHOS) genes, and PGC-1α gene expression. Overexpression of PGC-1α increased expression of OXPHOS and fatty-acid β-oxidation genes, ultimately leading to the potent induction of mitochondrial respiration and fatty-acid oxidation. PGC-1α gain of function also strongly induced numerous antioxidant genes and, importantly, protected RPE from oxidant-mediated cell death without altering RPE functions.

Conclusions: This study provides important insights into the metabolic changes associated with RPE functional maturation and identifies PGC-1α as a potent driver of RPE mitochondrial function and antioxidant capacity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1167/iovs.15-17758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788093PMC
March 2016

A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance.

Nat Med 2016 Apr 7;22(4):421-6. Epub 2016 Mar 7.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species, a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1α; encoded by Ppargc1a), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1α to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nm.4057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949205PMC
April 2016

Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice.

Skelet Muscle 2016 31;6. Epub 2016 Jan 31.

Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada ; Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5 Canada.

Background: Human genetic disorders and transgenic mouse models have shown that mitochondrial DNA (mtDNA) mutations and telomere dysfunction instigate the aging process. Epidemiologically, exercise is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of exercise are well established, the molecular mechanisms instigating these observations remain unclear.

Results: Endurance exercise reduces mtDNA mutation burden, alleviates multisystem pathology, and increases lifespan of the mutator mice, with proofreading deficient mitochondrial polymerase gamma (POLG1). We report evidence for a POLG1-independent mtDNA repair pathway mediated by exercise, a surprising notion as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here, we show that the tumor suppressor protein p53 translocates to mitochondria and facilitates mtDNA mutation repair and mitochondrial biogenesis in response to endurance exercise. Indeed, in mutator mice with muscle-specific deletion of p53, exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, or mitigate premature mortality.

Conclusions: Our data establish a new role for p53 in exercise-mediated maintenance of the mtDNA genome and present mitochondrially targeted p53 as a novel therapeutic modality for diseases of mitochondrial etiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13395-016-0075-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733510PMC
September 2016

PGC-1α induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle.

Circ Res 2014 Aug 9;115(5):504-17. Epub 2014 Jul 9.

From the Department of Medicine, Cardiovascular Institute (G.C.R., S.R., C.J., I.S.P., A.G., M.C.C., L.X.L., A.J., Z.A.), Center for Vascular Biology Research (J.A.N., K.C.S., D.B., H.D., W.C.A., Z.A.), and Department of Pathology (J.A.N., H.D.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

Rationale: Mechanisms of angiogenesis in skeletal muscle remain poorly understood. Efforts to induce physiological angiogenesis hold promise for the treatment of diabetic microvascular disease and peripheral artery disease but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and patients with diabetes mellitus. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. Peroxisome proliferation activator receptor-γ coactivator-1α (PGC-1α), a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle.

Objective: To test whether, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle.

Methods And Results: Here, we show that muscle PGC-1α robustly induces functional angiogenesis in adult, aged, and diabetic mice. The process involves the orchestration of numerous cell types and leads to patent, nonleaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of vascular endothelial growth factor alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 and the recruitment of macrophages. Secreted phosphoprotein 1 stimulates macrophages to secrete monocyte chemoattractant protein-1, which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in secreted phosphoprotein 1(-/-) mice leads to immature capillarization and blunted arteriolarization. Finally, adenoviral delivery of PGC-1α into skeletal muscle of either young or old and diabetic mice improved the recovery of blood flow in the murine hindlimb ischemia model of peripheral artery disease.

Conclusions: PGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.115.303829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524357PMC
August 2014

Running forward: new frontiers in endurance exercise biology.

Circulation 2014 Feb;129(7):798-810

Cardiovascular Institute and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.113.001590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981549PMC
February 2014

Hypoxic induction of vascular endothelial growth factor (VEGF) and angiogenesis in muscle by truncated peroxisome proliferator-activated receptor γ coactivator (PGC)-1α.

J Biol Chem 2014 Mar 6;289(13):8810-7. Epub 2014 Feb 6.

From the Cardiovascular Institute and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115.

The transcriptional coactivator peroxisome proliferator-activator receptor γ coactivator (PGC)-1α is required for full hypoxic induction of vascular endothelial growth factor (VEGF) in skeletal muscle cells. Under normoxic conditions, PGC-1α also strongly induces mitochondrial biogenesis, but PGC-1α does not activate this program under hypoxic conditions. How this specificity is achieved is not known. We show here that hypoxia specifically induces alternatively spliced species encoding for truncated forms of PGC-1α: NT-PGC-1α and PGC-1α4. NT-PGC-1α strongly induces VEGF expression, whereas having little effect on mitochondrial genes. Conditioned medium from cells expressing NT-PGC-1α robustly induces endothelial migration and tube formation, hallmarks of angiogenesis. Transgenic expression of PGC-1α4 in skeletal muscle in mice induces angiogenesis in vivo. Finally, knockdown of these PGC-1α isoforms and hypoxia-inducible factor-1α (HIF-1α) abrogates the induction of VEGF in response to hypoxia. NT-PGC-1α and/or PGC-1α4 thus confer angiogenic specificity to the PGC-1α-mediated hypoxic response in skeletal muscle cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M114.554394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979394PMC
March 2014

Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin.

Skelet Muscle 2014 Jan 22;4(1). Epub 2014 Jan 22.

Cardiovascular Institute, and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave, 02215 Boston, MA, USA.

Background: Duchenne muscle dystrophy (DMD) afflicts 1 million boys in the US and has few effective treatments. Constitutive transgenic expression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α improves skeletal muscle function in the murine "mdx" model of DMD, but how this occurs, or whether it can occur post-natally, is not known. The leading mechanistic hypotheses for the benefits conferred by PGC-1α include the induction of utrophin, a dystrophin homolog, and/or induction and stabilization of the neuromuscular junction.

Methods: The effects of transgenic overexpression of PGC-1β, a homolog of PGC-1α in mdx mice was examined using different assays of skeletal muscle structure and function. To formally test the hypothesis that PGC-1α confers benefit in mdx mice by induction of utrophin and stabilization of neuromuscular junction, PGC-1α transgenic animals were crossed with the dystrophin utrophin double knock out (mdx/utrn-/-) mice, a more severe dystrophic model. Finally, we also examined the effect of post-natal induction of skeletal muscle-specific PGC-1α overexpression on muscle structure and function in mdx mice.

Results: We show here that PGC-1β does not induce utrophin or other neuromuscular genes when transgenically expressed in mouse skeletal muscle. Surprisingly, however, PGC-1β transgenesis protects as efficaciously as PGC-1α against muscle degeneration in dystrophin-deficient (mdx) mice, suggesting that alternate mechanisms of protection exist. When PGC-1α is overexpressed in mdx/utrn-/- mice, we find that PGC-1α dramatically ameliorates muscle damage even in the absence of utrophin. Finally, we also used inducible skeletal muscle-specific PGC-1α overexpression to show that PGC-1α can protect against dystrophy even if activated post-natally, a more plausible therapeutic option.

Conclusions: These data demonstrate that PGC-1α can improve muscle dystrophy post-natally, highlighting its therapeutic potential. The data also show that PGC-1α is equally protective in the more severely affected mdx/utrn-/- mice, which more closely recapitulates the aggressive progression of muscle damage seen in DMD patients. The data also identify PGC-1β as a novel potential target, equally efficacious in protecting against muscle dystrophy. Finally, the data also show that PGC-1α and PGC-1β protect against dystrophy independently of utrophin or of induction of the neuromuscular junction, indicating the existence of other mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/2044-5040-4-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914847PMC
January 2014