scholarly journals Activin Signaling Regulates Autophagy and Cardiac Aging through mTORC2

2017 ◽  
Author(s):  
Kai Chang ◽  
Ping Kang ◽  
Ying Liu ◽  
Kerui Huang ◽  
Erika Taylor ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Tissue ◽  
Type I ◽  
Specific Expression ◽  
Cardiac Aging ◽  
Activin Signaling ◽  
Cardiac Health ◽  
Age Related ◽  
Heart Performance ◽  
Slow Heart Rate

AbstractAge-dependent loss of cardiac tissue homeostasis largely impacts heart performance and contributes significantly to cardiovascular diseases later in life. Cellular quality control machinery, such as autophagy/lysosome system, plays a crucial role in maintaining cardiac health and preventing age-induced cardiomyopathy and heart failure. However, how aging alters the autophagy/lysosome system to impact cardiac function remains largely unknown. Here using Drosophila heart as a model system, we show that activin signaling, a member of TGF-beta superfamily, negatively regulates cardiac autophagy and cardiac health during aging. We found that cardiac-specific knockdown of Daw, an activin-like protein in Drosophila, increased cardiac autophagy and prevented age-related cardiac dysfunction, including arrhythmia and bradycardia (slow heart rate). Inhibition of autophagy blocked Daw knockdown-mediated cardioprotection. Consistently, cardiac-specific expression of constitutively activated activin type I receptor Babo disrupted cardiac function at young ages. Intriguingly, the key autophagy regulator, mechanistic target of rapamycin complex 1 (mTORC1), was not involved in activin-mediated autophagy. Instead, activin signaling genetically interacted with Rictor, the key subunit of mTORC2, to regulate autophagy and cardiac aging. Knockdown of Daw increased the mRNA expression of Rictor and the phosphorylation of AKT in fly hearts. Finally, cardiac-specific silencing of Daw not only improved cardiac health, but also prolonged lifespan. Thus, our findings highlight an emerging role of activin signaling and mTORC2 in the regulation of autophagy and cardiac aging.

scholarly journals Effect of Cellular and ECM Aging on Human iPSC-derived Cardiomyocyte Performance, Maturity and Senescence

2020 ◽  
Author(s):  
S. Gulberk Ozcebe ◽  
Gokhan Bahcecioglu ◽  
Xiaoshan S. Yue ◽  
Pinar Zorlutuna
Keyword(s):  
Cardiac Function ◽  
Cardiac Tissue ◽  
Induced Pluripotent Stem Cell ◽  
State Function ◽  
Cardiac Aging ◽  
Induced Pluripotent ◽  
The Individual ◽  
Drug Responsiveness ◽  
Tissue Aging

AbstractCardiovascular diseases are the leading cause of death worldwide and their occurrence is highly associated with age. However, lack of knowledge in cardiac tissue aging is a major roadblock in devising novel therapies. Here, we studied the effects of cell and cardiac extracellular matrix (ECM) aging on the induced pluripotent stem cell (iPSC)-derived cardiomyocyte cell state, function, as well as response to myocardial infarction (MI)-mimicking stress conditions in vitro. Within 3-weeks, young ECM promoted proliferation and drug responsiveness in young cells, and induced cell cycle re-entry, and protection against stress in the aged cells. Adult ECM improved cardiac function, while aged ECM accelerated the aging phenotype, and impaired cardiac function and stress defense machinery of the cells. In summary, we have gained a comprehensive understanding of cardiac aging and highlighted the importance of cell-ECM interactions. This study is the first to investigate the individual effects of cellular and environmental aging and identify the biochemical changes that occur upon cardiac aging.

scholarly journals HSP27 Alleviates Cardiac Aging in Mice via a Mechanism Involving Antioxidation and Mitophagy Activation

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Shenglan Lin ◽  
Yana Wang ◽  
Xiaojin Zhang ◽  
Qiuyue Kong ◽  
Chuanfu Li ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Interstitial Fibrosis ◽  
Significant Decline ◽  
Oxygen Species ◽  
Prominent Feature ◽  
Wild Type ◽  
Specific Expression ◽  
Cardiac Aging ◽  
Striking Contrast

Aging-induced cardiac dysfunction is a prominent feature of cardiac aging. Heat shock protein 27 (HSP27) protects cardiac function against ischemia or chemical challenge. We hypothesized that HSP27 attenuates cardiac aging. Transgenic (Tg) mice with cardiac-specific expression of theHSP27gene and wild-type (WT) littermates were employed in the experiments. Echocardiography revealed a significant decline in the cardiac function of old WT mice compared with young WT mice. In striking contrast, the aging-induced impairment of cardiac function was attenuated in old Tg mice compared with old WT mice. Levels of cardiac aging markers were lower in old Tg mouse hearts than in old WT mouse hearts. Less interstitial fibrosis and lower contents of reactive oxygen species and ubiquitin-conjugated proteins were detected in old Tg hearts than in old WT hearts. Furthermore, old Tg hearts demonstrated lower accumulation of LC3-II and p62 than old WT hearts. Levels of Atg13, Vps34, and Rab7 were also higher in old Tg hearts than in old WT hearts. Additionally, old Tg hearts had higher levels of PINK1 and Parkin than old WT hearts, suggesting that mitophagy was activated in old Tg hearts. Taken together, HSP27 alleviated cardiac aging and this action involved antioxidation and mitophagy activation.

Engineered Membranes Improve Cardiac Function in Ischemic Rat Hearts

2010 ◽  
Author(s):  
Monica Sandri ◽  
Anna Tampieri ◽  
Joung H. Levialdi Ghiron ◽  
Gianluigi Condorelli
Keyword(s):  
Cardiac Function ◽  
Cardiac Tissue ◽  
Diglycidyl Ether ◽  
Beating Heart ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Heart Cell ◽  
Collagen Membrane ◽  
Heart Cells ◽  
Type I

In the relatively young field of cardiac tissue engineering, different biomaterials, methods and techniques have been tested for cardiac repair. In this study we examined the validity of a series of new preformed membrane scaffolds, based on collagen type I, for the transplantation of cardiac cells. One type of membrane, cross-linked with 1,4-butanediol diglycidyl ether (BDDGE) and fibronectin-enriched, gave rise to spontaneously beating heart cell constructs 5–9 days after seeding with neonatal rat cardiac cells. This membrane was then grafted, with and without beating cardiac cells, onto the infarcted area of rat models of heart failure. Seriate echocardiography, performed on rats before transplantation and at 4 and 8 weeks after transplantation, showed that rats that received collagen membranes with beating cells showed an improvement in cardiac function after 8 weeks. These results suggest that this new type of collagen membrane can be used as vector for the transplantation of beating heart cells to the injured myocardium, hence representing an important potential tool for cardiac tissue repair technologies.

scholarly journals Early differences in auditory processing relate to Autism Spectrum Disorder traits in infants with Neurofibromatosis Type I

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jannath Begum-Ali ◽  
◽  
Anna Kolesnik-Taylor ◽  
Isabel Quiroz ◽  
Luke Mason ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Auditory Processing ◽  
Neurofibromatosis Type ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Type I ◽  
Sensory Reactivity ◽  
Auditory Responses ◽  
Repetition Suppression ◽  
Age Related

Abstract Background Sensory modulation difficulties are common in children with conditions such as Autism Spectrum Disorder (ASD) and could contribute to other social and non-social symptoms. Positing a causal role for sensory processing differences requires observing atypical sensory reactivity prior to the emergence of other symptoms, which can be achieved through prospective studies. Methods In this longitudinal study, we examined auditory repetition suppression and change detection at 5 and 10 months in infants with and without Neurofibromatosis Type 1 (NF1), a condition associated with higher likelihood of developing ASD. Results In typically developing infants, suppression to vowel repetition and enhanced responses to vowel/pitch change decreased with age over posterior regions, becoming more frontally specific; age-related change was diminished in the NF1 group. Whilst both groups detected changes in vowel and pitch, the NF1 group were largely slower to show a differentiated neural response. Auditory responses did not relate to later language, but were related to later ASD traits. Conclusions These findings represent the first demonstration of atypical brain responses to sounds in infants with NF1 and suggest they may relate to the likelihood of later ASD.

scholarly journals Electromyographic activation patterns during swallowing in older adults

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jin Young Ko ◽  
Hayoung Kim ◽  
Joonyoung Jang ◽  
Jun Chang Lee ◽  
Ju Seok Ryu
Keyword(s):  
Older Adults ◽  
Viscous Fluid ◽  
Muscle Activation ◽  
Fatty Infiltration ◽  
Liquid Volume ◽  
Type I ◽  
Type Ii ◽  
Activation Patterns ◽  
Muscle Activation Patterns ◽  
Age Related

AbstractAge-related weakness due to atrophy and fatty infiltration in oropharyngeal muscles may be related to dysphagia in older adults. However, little is known about changes in the oropharyngeal muscle activation pattern in older adults. This was a prospective and experimental study. Forty healthy participants (20 older [> 60 years] and 20 young [< 60 years] adults) were enrolled. Six channel surface electrodes were placed over the bilateral suprahyoid (SH), bilateral retrohyoid (RH), thyrohyoid (TH), and sternothyroid (StH) muscles. Electromyography signals were then recorded twice for each patient during swallowing of 2 cc of water, 5 cc of water, and 5 cc of a highly viscous fluid. Latency, duration, and peak amplitude were measured. The activation patterns were the same, in the order of SH, TH, and StH, in both groups. The muscle activation patterns were classified as type I and II; the type I pattern was characterized by a monophasic shape, and the type II comprised a pre-reflex phase and a main phase. The oropharyngeal muscles and SH muscles were found to develop a pre-reflex phase specifically with increasing volume and viscosity of the swallowed fluid. Type I showed a different response to the highly viscous fluid in the older group compared to that in the younger group. However, type II showed concordant changes in the groups. Therefore, healthy older people were found to compensate for swallowing with a pre-reflex phase of muscle activation in response to increased liquid volume and viscosity, to adjust for age-related muscle weakness.

scholarly journals TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2

Autophagy ◽  
2019 ◽  
Vol 16 (10) ◽  
pp. 1807-1822 ◽  
Author(s):  
Kai Chang ◽  
Ping Kang ◽  
Ying Liu ◽  
Kerui Huang ◽  
Ting Miao ◽  
...  
Keyword(s):  
Activin Signaling ◽  
Cardiac Health ◽  
Age Dependent

scholarly journals Protein carbamylation is a hallmark of aging

2015 ◽  
Vol 113 (5) ◽  
pp. 1191-1196 ◽  
Author(s):  
Laëtitia Gorisse ◽  
Christine Pietrement ◽  
Vincent Vuiblet ◽  
Christian E. H. Schmelzer ◽  
Martin Köhler ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Type I Collagen ◽  
Accumulation Rate ◽  
Mammalian Species ◽  
Type I ◽  
Protective Mechanisms ◽  
Age Related ◽  
Tissue Damages ◽  
Carboxymethyl Lysine ◽  
Tissue Alterations

Aging is a progressive process determined by genetic and acquired factors. Among the latter are the chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, which are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of isocyanate derived from urea dissociation or myeloperoxidase-mediated catabolism of thiocyanate to free amino groups of proteins. This modification is considered an adverse reaction, because it induces alterations of protein and cell properties. It has been shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes, but nothing is known to date about tissue protein carbamylation during aging. To address this issue, we evaluated homocitrulline rate, the most characteristic carbamylation-derived product (CDP), over time in skin of mammalian species with different life expectancies. Our results show that carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of carbamylated proteins. Because of their remarkably long half-life, matrix proteins, like type I collagen and elastin, are preferential targets. Interestingly, the accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. In addition, homocitrulline accumulates more intensely than carboxymethyl-lysine, one of the major advanced glycation end products, suggesting the prominent role of carbamylation over glycoxidation reactions in age-related tissue alterations. Thus, protein carbamylation may be considered a hallmark of aging in mammalian species that may significantly contribute in the structural and functional tissue damages encountered during aging.

scholarly journals Age-Related Changes in Molecular and Whole Muscle Function: Role of Fat Content?

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 141-141
Author(s):  
Joseph Gordon III ◽  
Nicholas Remillard ◽  
Chad Straight ◽  
Rajakumar Nagarajan ◽  
Bruce Damon ◽  
...  
Keyword(s):  
Older Adults ◽  
Molecular Mechanisms ◽  
Fat Content ◽  
Fat Deposition ◽  
Muscle Size ◽  
Type I ◽  
Contraction Velocity ◽  
Age Related ◽  
Whole Muscle ◽  
Age Related Changes

Abstract Decreases in muscle size and function are a general consequence of old age; the precise mechanisms of these changes remain unclear. Recent studies suggest that fat deposition in muscle may also contribute to dysfunction in older adults. Fat content was quantified in the quadriceps, and its effects on function in healthy young (21-45 y) and older (65-75 y) men and women (n=44) of comparable physical activity were compared. A subset of the young matched with the older group for muscle fat content were also examined. Peak fat-free whole muscle cross-sectional area (mCSA; cm2), volume (MV; cm3), fat content (fat fraction, FF; %), specific torque (Nm/mCSA) and peak contraction velocity (Nm∙s-1) were determined using fat-water magnetic resonance imaging and dynamometry (0-300□∙s-1). To examine potential molecular mechanisms of muscle weakness, vastus lateralis biopsies were obtained (n=31) and cross-bridge kinetics of type I and II fibers were determined. FF was higher in older adults than young (8.4±1.2% (SE), 7.6±1.4; p=0.03), while mCSA (48.9±10.4 vs. 64.2±17.3), MV (1536±532 vs. 2112±708), specific torque (2.6±0.4 vs. 3.2±0.4), and peak voluntary contraction velocity (422±20 vs. 441±23) were lower in older than young (p&lt;0.01). Type II fiber myosin attachment rate was slower and attachment time longer in older muscle (p&lt;0.017), providing a potential mechanism for the slowing of peak contraction velocity with age. Notably, differences at the whole muscle and molecular levels remained for the subset of young and older groups matched for FF, suggesting that fat deposition in muscle does not exacerbate age-related changes in function.

Age-related changes in renal and hepatic cellular mechanisms associated with variations in rat serum thyroid hormone levels

2008 ◽  
Vol 294 (6) ◽  
pp. E1160-E1168 ◽  
Author(s):  
Elena Silvestri ◽  
Assunta Lombardi ◽  
Pieter de Lange ◽  
Luigi Schiavo ◽  
Antonia Lanni ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Total Protein ◽  
Protein Level ◽  
Monocarboxylate Transporter ◽  
Type I ◽  
Peripheral Tissues ◽  
Protein Levels ◽  
Age Related ◽  
Liver And Kidney ◽  
Age Related Changes

Aging is associated with changes in thyroid gland physiology. Age-related changes in the contribution of peripheral tissues to thyroid hormone serum levels have yet to be systematically assessed. Here, we investigated age-related alterations in the contributions of the liver and kidney to thyroid hormone homeostasis using 6-, 12-, and 24-mo-old male Wistar rats. A significant and progressive decline in plasma thyroxine occurred with age, but triiodothyronine (T3) was decreased only at 24 mo. This was associated with an unchanged protein level of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) in the kidney and with a decreased MCT8 level in the liver at 24 mo. Hepatic type I deiodinase (D1) protein level and activity declined progressively with age. Renal D1 levels were decreased at both 12 and 24 mo but D1 activity was decreased only at 24 mo. In the liver, no changes occurred in thyroid hormone receptor (TR) TRα1, whereas a progressive increase in TRβ1 occurred at both mRNA and total protein levels. In the kidney, both TRα1 and TRβ1 mRNA and total protein levels were unchanged between 6 and 12 mo but increased at 24 mo. Interestingly, nuclear TRβ1 levels were decreased in both liver and kidney at 12 and 24 mo, whereas nuclear TRα1 levels were unchanged. Collectively, our data show differential age-related changes among hepatic and renal MCT8 and D1 and TR expressions, and they suggest that renal D1 activity is maintained with age to compensate for the decrease in hepatic T3 production.

Abstract 269: Miofibroblast Tgf-beta Signaling in a Proteotoxic Mouse Model

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Bidur Bhandary ◽  
Qinghang Meng ◽  
Hanna Osinska ◽  
Kritton Shay-Winkler ◽  
James Gulick ◽  
...  
Keyword(s):  
Heart Disease ◽  
Mouse Model ◽  
Cardiac Function ◽  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Prolonged Survival ◽  
Tgfβ Signaling ◽  
Specific Expression ◽  
Western Blots

Introduction: Transforming Growth Factor Beta (TGFβ) is an important cytokine in mediating the fibrogenic response and, in particular, cardiac fibrosis. Extensive fibrosis accompanies the cardiac remodeling that occurs during development of the protein conformation-based disease caused by cardiomyocyte-specific expression of a mutant, small, heat shock-like protein and chaperone, aB crystallin (CryABR120G). During the onset of fibrosis, fibroblasts are activated to the so-called “myofibroblast” state and TGFβ binding is thought to mediate an essential signaling pathway underlying this process. Our central hypothesis is that TGFβ signaling processes that result in significant cardiac fibrosis in a mouse model of proteotoxic heart disease are mediated by cardiac fibroblasts, rather than cardiomyocytes. Here, we have partially ablated TGFβ signaling only in cardiac myofibroblasts to observe if cardiac fibrosis is reduced. Aims and Methods: The objective of this study was to understand the contributions of fibroblast-derived TGFβ signaling to the development of cardiac fibrosis in a proteotoxic mouse model that results in significant cardiac fibrosis. To test the hypothesis we partially deleted the myofibroblast specific canonical and non-canonical signaling by crossing CryAB R120G mice with Tgfbr1 or Tgfbr2 floxed mice. The double transgene containing mice were further crossed with activated myofibroblast specific Cre mice in which Cre expression was driven off the periostin promoter. Echocardiography, Masson’s Trichome staining, PCR arrays, IHC and western blots were performed to characterize the fibrotic progression in CryAB R120G transgenic mice. Results: We observed that myofibroblast-targeted partial knockdown of Tgf βr1 signaling prolonged survival, modestly reducing fibrosis and improving cardiac function . Similarly, Tgf βr2 partial knockdown prolonged survival, modestly reducing fibrosis without improving cardiac function during fibrosis development in CryAB R120G mice. Conclusion: These findings suggest that, in a model of proteotoxic heart disease, myofibroblast based TGFβ signaling in the heart may contribute to cardiac hypertrophy/dysfunction but cannot account entirely for the fibrotic response.

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