Karla Maria Pereira Pires

University of Utah

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Samuel Santos Valença

Universidade Federal do Rio de Janeiro

Sihem Boudina

University of Utah

Luís Cristóvão Pôrto

Universidade do Estado do Rio de Janeiro

Manuella Lanzetti

Universidade Federal do Rio de Janeiro

E. Dale Abel

University of California, Los Angeles

Renata Tiscoski Nesi

Pontifícia Universidade Católica do Paraná

Márcio Buffolo

University of Utah

Marina Valente Barroso

Architecture et Réactivité de l'arN

Walter A. Zin

Petronas (Malaysia)

J. David Symons

University of Utah

Cooperative Institutions

University of Utah

Universidade Federal do Rio de Janeiro

Universidade do Estado do Rio de Janeiro

University of Iowa

Fraternal Order of Eagles

George E. Wahlen Department of VA Medical Center

University of Freiburg

Diabetes Australia

Geriatric Research Education and Clinical Center

Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

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Late‐In‐Life Treadmill‐Training Ameliorates the Decline in Cardiac Autophagy Associated with Aging in Mice

The FASEB Journal (2019)

Jae Min Cho Caroline Ramous Maria Sara de Lima Coutinho Mattera Michele Hansen Karla Maria Pereira Pires

Protein aggregates accumulate and organelles become damaged and/or dysfunctional during the process of aging. A progressive loss of the cellular quality control mechanism autophagy contributes to this age‐associated decline in cellular function in many organs. Evidence for an age‐associated repression in cardiac autophagy is not consistent. We hypothesized that 24‐month old (old) male C57Bl6/J mice exhibit repressed autophagosome formation in the heart, myocardial dysfunction, and reduced exercise capacity vs. 6‐month old (adult) mice. First, cardiac lysates from old mice displayed reduced (p<0.05) accumulation of LC3II/GAPDH and degradation of p62 vs. adult animals (n=12 per group). Second, the lysosomal acidification inhibitor chloroquine (CQ) induced accrual (p<0.05) of LC3II/GAPDH and p62 in hearts from adult but not old mice (n=7 per group). Third, left ventricular mass was greater (p<0.05), and indices of systolic, diastolic, and global left ventricular function (transthoracic echocardiography) were impaired, in old vs. adult animals (n=12 per group). Finally, maximal workload performed during a treadmill‐test was less (p<0.05) in aged (n=11) vs. adult (n=12) mice. To determine whether late‐in‐life exercise training induces cardiac autophagy, separate cohorts of male mice completed a progressive‐resistance treadmill‐running program (old‐ETR) or remained sedentary (old‐SED) from 21–24 months. Body composition, exercise performance during a maximal workload test, soleus muscle citrate synthase (CS) activity, indices of cardiac antioxidant enzyme activity, markers of cardiac autophagy, and indices of myocardial function, all improved (p<0.05) in old‐ETR (n=11) vs. old‐SED (n=12) mice. These data are the first to demonstrate that markers of cardiac autophagy are elevated, and indices of myocardial function are improved, in old mice that complete a treadmill‐training regimen that is sufficient to increase skeletal muscle CS activity and maximal exercise capacity. These data provide strong proof of concept to evaluate cause and effect relationships among exercise‐training, myocardial. Support or Funding Information UU Research Fellowship (JMC); APS UGRF (CR); AHA17POST33670663 (SKP); NIHRO1DK098646‐01A1, NIHRO1DK099110, AHA16GRANT30990018 (SB); AHA16GRNT31050004, NIH RO3AGO52848, NIH RO1HL141540 (JDS). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Treadmill

Senescence

10.1096/fasebj.2019.33.1_supplement.693.4

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Late‐In‐Life Treadmill‐Training Improves Autophagy, Protein Clearance, and Contractile Function in Mouse Hearts

The FASEB Journal (2020)

Kellsey Ly Jae Min Cho Michele Hansen Caroline Ramous Lauren Thompson

Evidence exists that a progressive decline of the cellular quality control mechanism called macroautophagy occurs during the process of primary aging. This leads to the accumulation of protein aggregates (i.e., proteotoxicity) that would otherwise be transported to and degraded in the lysosome. Post‐mitotic cells like cardiomyocytes rely heavily on macroautophagy because of their inability to clear defective proteins via cell division. While voluntary wheel running improves cardiac autophagy, lessens cardiac proteotoxicity, and attenuates myocardial dysfunction in mice with desmin‐related cardiomyopathy ( Bhuiyan et al., JCI, 2013 ), the ability for a physiological intervention to improve these indexes in aged mice is unknown. We hypothesized that late‐in‐life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs adult mice. As expected, 24‐month old male C57Bl6 mice (old) exhibited repressed autophagosome formation in the heart, myocardial protein aggregate accumulation, systolic and diastolic dysfunction, and reduced exercise capacity vs. 6‐month old (adult) mice (all p< 0.05; n=10 per group) Separate cohorts of 21 month old mice completed a 10‐week progressive resistance / duration treadmill‐running program (old‐ETR) that improved (all p<0.05): (i) body composition; (ii) maximal workload capacity; and (iii) soleus muscle citrate synthase activity vs. age‐matched sedentary mice (old‐SED). Of note, (iv) mRNA and protein expression of autophagy markers indicated trafficking of the autophagosome to the lysosome increased, (v) protein aggregate clearance improved, and (vi) contractile function was enhanced (all p<0.05), in hearts from old‐ETR vs. old‐SED mice. Dietary maneuvers (e.g., caloric restriction, nutraceutical supplementation) and pharmacological interventions (e.g., rapamycin) are reported to elevate myocardial autophagy and mitigate / reverse age‐associated cardiac dysfunction. Here we show the first evidence that a physiological intervention i.e., late‐in‐life exercise training, improves autophagic flux, protein aggregate clearance, and contractile function in hearts from aged mice. Support or Funding Information KL [APS STRIDE, UU Undergraduate Research Program (UROP)], JMC (UU Research Fellowship), SKP (AHA 17POST33670663), CR (APS UGRF, UROP), LT (UROP), SB (NIDDK R01‐DK‐098646‐01A1, R01‐DK‐099110, AHA 16GRNT30990018), JDS (AHA16GRNT31050004, NIH RO3AGO52848, NIHRO1HL141540).

Proteotoxicity

TFEB

Protein turnover

10.1096/fasebj.2020.34.s1.04890

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Antioxidant action of propolis on mouse lungs exposed to short-term cigarette smoke

Bioorganic & Medicinal Chemistry (2013)

Alan Aguiar Lopes Thiago Santos Ferreira Renata Tiscoski Nesi Manuella Lanzetti Karla Maria Pereira Pires

Propolis is a natural product with antioxidant properties. In this study, we tested the efficacy of propolis against acute lung inflammation (ALI) caused by cigarette smoke (CS). C57BL6 male mice were exposed to CS and treated with propolis (200 mg/kg orally, CS+P) or only with propolis (P). A Control group treated with propolis was sham-smoked (Control+P). We collected the lungs for histological and biochemical analyses. We observed an increase in alveolar macrophages and neutrophils in the CS group compared with the Control+P. These counts reduced in the CS+P group compared to the CS group. The treatment with propolis normalized all biochemical parameters in the CS+P group compared with the CS group, including nitrite, myeloperoxidase level, antioxidant enzyme activities (superoxide dismutase, catalase and glutathione peroxidase), reduced glutathione/oxidized glutathione ratio and malondialdehyde. Additionally, TNF-α expression reduced in the CS+P group when compared with the CS group. These data imply a potential antioxidant and anti-inflammatory role for propolis with regard to ALI caused by CS in mice.

Propolis

Malondialdehyde

10.1016/j.bmc.2013.10.044

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Reduced Mitochondrial Oxidative Stress Impairs Brown Adipose Tissue-Mediated Thermogenesis in Mice

Free Radical Biology and Medicine (2016)

Karla Maria Pereira Pires Márcio Buffolo Samuel Santos Valença Peter S. Rabinovitch Sihem Boudina

Thermogenin

Nitrotyrosine

10.1016/j.freeradbiomed.2016.10.468

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Pulmonary and hepatic injury after sub-chronic exposure to sublethal doses of microcystin-LR

Toxicon (2016)

Giovanna Marcella Cavalcante Carvalho Vinícius Rosa Oliveira Natália Casquilho Andressa Cristine Pereira Araujo Raquel Soares

Steatosis

10.1016/j.toxicon.2016.01.066

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Treatment with a SOD mimetic reduces visceral adiposity, adipocyte death, and adipose tissue inflammation in high fat‐fed mice

Obesity (2013)

Karla Maria Pereira Pires Olesya Ilkun Marina Valente Barroso Sihem Boudina

Objective Obesity is associated with enhanced reactive oxygen species (ROS) accumulation in adipose tissue. However, a causal role for ROS in adipose tissue expansion after high fat feeding is not established. The aim of this study is to investigate the effect of the cell permeable superoxide dismutase mimetic and peroxynitrite scavenger Mn(III)tetrakis(4‐benzoic acid)porphyrin chloride (MnTBAP) on adipose tissue expansion and remodeling in response to high fat diet (HFD) in mice. Design and Methods Male C57BL/6j mice were fed normal chow or high fat diet (HFD) and treated with saline or MnTBAP for 5 weeks. The effects of MnTBAP on body weights, whole body energy expenditure, adipose tissue morphology, and gene expression were determined. Results MnTBAP attenuated weight gain and adiposity through a reduction in adipocyte hypertrophy, adipogenesis, and fatty acid uptake in epididymal (eWAT) but not in inguinal (iWAT) white adipose tissue. Furthermore, MnTBAP reduced adipocyte death and inflammation in eWAT and diminished circulating levels of free fatty acids and leptin. Despite these improvements, the development of systemic insulin resistance and diabetes after HFD was not prevented with MnTBAP treatment. Conclusions Taken together, these data suggest a causal role for ROS in the development of diet‐induced visceral adiposity but not in the development of insulin resistance and type 2 diabetes.

10.1002/oby.20465

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Abstract MP248: Sequestrosome1/p62 Regulates Redox Homeostasis Via The Nrf2-keap1 Pathway In The Murine Heart

Circulation Research (2021)

Amir Nima Fatahian Rajeshwary Ghosh Karla Maria Pereira Pires Tariq Mosleh Vishaka Vinod

Sequestosome1 (p62) is a multifunctional signaling molecule and an autophagy adaptor protein. Previous work demonstrated that mice with whole-body p62 knockout recapitulated many detrimental features of aging. Of note, these mice developed late onset obesity and systemic abnormalities that could have contributed to their aging phenotype. Multiple studies have also shown that cardiac dysfunction can be linked to an increase in oxidative stress. The Nrf2-Keap1 pathway is critical for protection against oxidative stress and p62 has been shown to interact with Keap1, thus allowing Nrf2 activation to induce anti-oxidant responses. However, the role of p62 in the heart is not well known. We tested the hypothesis that p62 plays an important homeostatic role in the heart through the regulation of redox homeostasis via the Nrf2-Keap1 pathway. Wild-type and cardiomyocytes-specific p62 knockout (cp62 KO) mice at 8 weeks and 60 weeks of age were used. At 8 weeks, cp62KO mice exhibited mild but significant contractile dysfunction compared to the wild-type controls. By 60 weeks, the KO mice developed cardiac hypertrophy, fibrosis and increased oxidative stress. cp62 KO hearts had decreased Nrf2 nuclear translocation and activation as evidenced by a 50% (p<0.005) reduction in the expression of the Nrf2 target glutathione S-transferase A4 ( Gsta2 ) gene. These findings were further validated by transcriptomic analysis followed by KEGG pathway analysis, which indicated that redox pathways were altered in the 60-week p62 null hearts. To examine the mechanisms involved in p62 regulation of Nrf2-Keap signaling, we utilized rat cardiac H9c2 myoblasts. Loss of p62 using p62 siRNA in H9c2 cells resulted in decreased Nrf2 levels and increased oxidative stress. These pathological consequences of suppressing p62 could be attributed to increased Nrf2 degradation via the proteasome. Together, these results reveal a previously uncharacterized role for p62 in the maintenance of cardiac redox signaling in the mouse heart.

KEAP1

Knockout mouse

Homeostasis

Conditional gene knockout

10.1161/res.129.suppl_1.mp248

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Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function

The EMBO Journal (2024)

Quan‐Jiang Zhang Zhonggang Li Qiuxia Li Samuel A.J. Trammell Mark S. Schmidt

Abstract Impaired autophagy is known to cause mitochondrial dysfunction and heart failure, in part due to altered mitophagy and protein quality control. However, whether additional mechanisms are involved in the development of mitochondrial dysfunction and heart failure in the setting of deficient autophagic flux remains poorly explored. Here, we show that impaired autophagic flux reduces nicotinamide adenine dinucleotide (NAD + ) availability in cardiomyocytes. NAD + deficiency upon autophagic impairment is attributable to the induction of nicotinamide N-methyltransferase (NNMT), which methylates the NAD + precursor nicotinamide (NAM) to generate N-methyl-nicotinamide (MeNAM). The administration of nicotinamide mononucleotide (NMN) or inhibition of NNMT activity in autophagy-deficient hearts and cardiomyocytes restores NAD + levels and ameliorates cardiac and mitochondrial dysfunction. Mechanistically, autophagic inhibition causes the accumulation of SQSTM1, which activates NF-κB signaling and promotes NNMT transcription. In summary, we describe a novel mechanism illustrating how autophagic flux maintains mitochondrial and cardiac function by mediating SQSTM1-NF-κB-NNMT signaling and controlling the cellular levels of NAD + .

Nicotinamide mononucleotide

10.1038/s44318-023-00009-w

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Late‐in‐life treadmill training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts

Aging Cell (2021)

Jae Min Cho Seul‐Ki Park Rajeshwary Ghosh Kellsey Ly Caroline Ramous

Abstract Protein quality control mechanisms decline during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age‐associated cardiac dysfunction. Macroautophagy is the process by which post‐mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late‐in‐life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs. adult mice. As expected, 24‐month‐old male C57BL/6J mice (old) exhibited repressed autophagosome formation and protein aggregate accumulation in the heart, systolic and diastolic dysfunction, and reduced exercise capacity vs. 8‐month‐old (adult) mice (all p < 0.05). To investigate the influence of late‐in‐life exercise training, additional cohorts of 21‐month‐old mice did (old‐ETR) or did not (old‐SED) complete a 3‐month progressive resistance treadmill running program. Body composition, exercise capacity, and soleus muscle citrate synthase activity improved in old‐ETR vs. old‐SED mice at 24 months (all p < 0.05). Importantly, protein expression of autophagy markers indicate trafficking of the autophagosome to the lysosome increased, protein aggregate clearance improved, and overall function was enhanced (all p < 0.05) in hearts from old‐ETR vs. old‐SED mice. These data provide the first evidence that a physiological intervention initiated late‐in‐life improves autophagic flux, protein aggregate clearance, and contractile performance in mouse hearts.

Autophagosome

Protein turnover

Endurance Training

sed

10.1111/acel.13467

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Adipocyte-Specific Deletion of Manganese Superoxide Dismutase Protects From Diet-Induced Obesity Through Increased Mitochondrial Uncoupling and Biogenesis

Diabetes (2016)

Yong Hwan Han Márcio Buffolo Karla Maria Pereira Pires Shaobo Pei Philipp E. Scherer

Obesity and insulin resistance are associated with oxidative stress (OS). The causal role of adipose OS in the pathogenesis of these conditions is unknown. To address this issue, we generated mice with an adipocyte-selective deletion of manganese superoxide dismutase (MnSOD). When fed a high-fat diet (HFD), the AdSod2 knockout (KO) mice exhibited less adiposity, reduced adipocyte hypertrophy, and decreased circulating leptin. The resistance to diet-induced adiposity was the result of an increased metabolic rate and energy expenditure. Furthermore, palmitate oxidation was elevated in the white adipose tissue (WAT) and brown adipose tissue of AdSod2 KO mice fed an HFD, and the expression of key fatty acid oxidation genes was increased. To gain mechanistic insight into the increased fat oxidation in HFD-fed AdSod2 KO mice, we quantified the mitochondrial function and mitochondrial content in WAT and found that MnSOD deletion increased mitochondrial oxygen consumption and induced mitochondrial biogenesis. This effect was preserved in cultured adipocytes from AdSod2 KO mice in vitro. As expected from the enhanced fat oxidation, circulating levels of free fatty acids were reduced in the HFD-fed AdSod2 KO mice. Finally, HFD-fed AdSod2 KO mice were protected from hepatic steatosis, adipose tissue inflammation, and glucose and insulin intolerance. Taken together, these results demonstrate that MnSOD deletion in adipocytes triggered an adaptive stress response that activated mitochondrial biogenesis and enhanced mitochondrial fatty acid oxidation, thereby preventing diet-induced obesity and insulin resistance.

10.2337/db16-0283

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Citations (83)