scholarly journals BECN1 F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner

2022 ◽  
Author(s):  
Salwa Sebti ◽  
Zhongju Zou ◽  
Michael U Shiloh
Keyword(s):  
Skeletal Muscle ◽  
Model Organisms ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Multiple Model ◽  
Wild Type ◽  
Age Related ◽  
Organ Specific ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

Autophagy is necessary for lifespan extension in multiple model organisms and autophagy dysfunction impacts age-related phenotypes and diseases. Introduction of an F121A mutation into the essential autophagy protein BECN1 constitutively increases basal autophagy in young mice and reduces cardiac and renal age-related changes in longer-lived Becn1F121A mutant mice. However, both autophagic and lysosomal activity have been described to decline with age. Thus, whether autophagic flux is maintained during aging and whether it is enhanced in Becn1F121A mice is unknown. Here we demonstrate that old wild type mice maintained functional autophagic flux in heart, kidney and skeletal muscle but not liver, and old Becn1F121A mice had increased autophagic flux in those same organs compared to wild type. In parallel, Becn1F121A mice were not protected against age-associated hepatic phenotypes but demonstrated reduced skeletal muscle fiber atrophy. These findings identify an organ-specific role for the ability of autophagy to impact organ aging phenotypes.

Abstract 123: Age-Related Endothelial Senescence is Driven by Thrombospondin-1-Activated NADPH Oxidase Nox1

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Daniel N Meijles ◽  
Imad Al Ghouleh ◽  
Sanghamitra Sahoo ◽  
Jefferson H Amaral ◽  
Heather Knupp ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Vascular Diseases ◽  
Dependent Manner ◽  
Wild Type ◽  
Molecular Control ◽  
Redox Biology ◽  
Age Related ◽  
P53 Activation

Organismal aging represents an independent risk factor underlying many vascular diseases, including systemic and pulmonary hypertension, and atherosclerosis. While the mechanisms driving aging are largely elusive, a steady persistent increase in tissue oxidative stress has been associated with senescence. Previously we showed TSP1 elicits NADPH oxidase (Nox)-dependent vascular smooth muscle cell oxidative stress. However mechanisms by which TSP1 affects endothelial redox biology are unknown. Here, we tested the hypothesis that TSP1 induces endothelial oxidative stress-linked senescence in aging. Using rapid autopsy disease-free human pulmonary (PA) artery, we identified a significant positive correlation between age, protein levels of TSP1, Nox1 and the cell-cycle repressor p21cip (p<0.05). Age also positively associated with increased Amplex Red-detected PA hydrogen peroxide levels (p<0.05). Moreover, treatment of human PA endothelial cells (HPAEC) with TSP1 (2.2nM; 24h) increased expression (~1.9 fold; p<0.05) and activation of Nox1 (~1.7 fold; p<0.05) compared to control, as assessed by Western blot and SOD-inhibitable cytochrome c reduction. Western blotting and immunofluorescence showed a TSP1-mediated increase in p53 activation, indicative of the DNA damage response. Moreover, TSP1 significantly increased HPAEC senescence in a p53/p21cip/Rb-dependent manner, as assessed by immunofluorescent detection of subcellular localization and senescence-associated β-galactosidase staining. To explore this pathway in vivo, middle-aged (8-10 month) wild-type and TSP1-null mice were utilized. In the TSP1-null, reduced lung senescence, oxidative stress, Nox1 levels and p21cip expression were observed compared to wild-type supporting findings in human samples and cell experiments. Finally, prophylactic treatment with specific Nox1 inhibitor NoxA1ds (10μM) attenuated TSP1-induced HPAEC ROS, p53 activation, p21cip expression and senescence. Taken together, our results provide molecular insight into the functional interplay between TSP1 and Nox1 in the regulation of endothelial senescence, with implications for molecular control of the aging process.

scholarly journals Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice

2020 ◽  
Vol 117 (38) ◽  
pp. 23925-23931
Author(s):  
Karoline Degenhardt ◽  
Jessica Wagner ◽  
Angelos Skodras ◽  
Michael Candlish ◽  
Anna Julia Koppelmann ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Vascular Dysfunction ◽  
Upper Body ◽  
Dependent Manner ◽  
Wild Type ◽  
Brain Vasculature ◽  
Cerebrovascular Function ◽  
Age Related ◽  
Novel Approach ◽  
Cerebrovascular Dysfunction

Medin is the most common amyloid known in humans, as it can be found in blood vessels of the upper body in virtually everybody over 50 years of age. However, it remains unknown whether deposition of Medin plays a causal role in age-related vascular dysfunction. We now report that aggregates of Medin also develop in the aorta and brain vasculature of wild-type mice in an age-dependent manner. Strikingly, genetic deficiency of the Medin precursor protein, MFG-E8, eliminates not only vascular aggregates but also prevents age-associated decline of cerebrovascular function in mice. Given the prevalence of Medin aggregates in the general population and its role in vascular dysfunction with aging, targeting Medin may become a novel approach to sustain healthy aging.

scholarly journals FOXO signaling is required for disuse muscle atrophy and is directly regulated by Hsp70

2010 ◽  
Vol 298 (1) ◽  
pp. C38-C45 ◽  
Author(s):  
Sarah M. Senf ◽  
Stephen L. Dodd ◽  
Andrew R. Judge
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Fiber ◽  
Muscle Wasting ◽  
Dominant Negative ◽  
Disuse Muscle Atrophy ◽  
Rat Soleus Muscle ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

The purpose of the current study was to determine whether heat shock protein 70 (Hsp70) directly regulates forkhead box O (FOXO) signaling in skeletal muscle. This aim stems from previous work demonstrating that Hsp70 overexpression inhibits disuse-induced FOXO transactivation and prevents muscle fiber atrophy. However, although FOXO is sufficient to cause muscle wasting, no data currently exist on the requirement of FOXO signaling in the progression of physiological muscle wasting, in vivo. In the current study we show that specific inhibition of FOXO, via expression of a dominant-negative FOXO3a, in rat soleus muscle during disuse prevented >40% of muscle fiber atrophy, demonstrating that FOXO signaling is required for disuse muscle atrophy. Subsequent experiments determined whether Hsp70 directly regulates FOXO3a signaling when independently activated in skeletal muscle, via transfection of FOXO3a. We show that Hsp70 inhibits FOXO3a-dependent transcription in a gene-specific manner. Specifically, Hsp70 inhibited FOXO3a-induced promoter activation of atrogin-1, but not MuRF1. Further studies showed that a FOXO3a DNA-binding mutant can activate MuRF1, but not atrogin-1, suggesting that FOXO3a activates these two genes through differential mechanisms. In summary, FOXO signaling is required for physiological muscle atrophy and is directly inhibited by Hsp70.

scholarly journals Satellite cell content is specifically reduced in type II skeletal muscle fibers in the elderly

2007 ◽  
Vol 292 (1) ◽  
pp. E151-E157 ◽  
Author(s):  
Lex B. Verdijk ◽  
René Koopman ◽  
Gert Schaart ◽  
Kenneth Meijer ◽  
Hans H. C. M. Savelberg ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fiber ◽  
Fiber Type ◽  
The Elderly ◽  
Type I ◽  
Type Ii ◽  
Fiber Area ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy ◽  
Type Ii Fibers

Satellite cells (SC) are essential for skeletal muscle growth and repair. Because sarcopenia is associated with type II muscle fiber atrophy, we hypothesized that SC content is specifically reduced in the type II fibers in the elderly. A total of eight elderly (E; 76 ± 1 yr) and eight young (Y; 20 ± 1 yr) healthy males were selected. Muscle biopsies were collected from the vastus lateralis in both legs. ATPase staining and a pax7-antibody were used to determine fiber type-specific SC content (i.e., pax7-positive SC) on serial muscle cross sections. In contrast to the type I fibers, the proportion and mean cross-sectional area of the type II fibers were substantially reduced in E vs. Y. The number of SC per type I fiber was similar in E and Y. However, the number of SC per type II fiber was substantially lower in E vs. Y (0.044 ± 0.003 vs. 0.080 ± 0.007; P < 0.01). In addition, in the type II fibers, the number of SC relative to the total number of nuclei and the number of SC per fiber area were also significantly lower in E. This study is the first to show type II fiber atrophy in the elderly to be associated with a fiber type-specific decline in SC content. The latter is evident when SC content is expressed per fiber or per fiber area. The decline in SC content might be an important factor in the etiology of type II muscle fiber atrophy, which accompanies the loss of skeletal muscle with aging.

scholarly journals Serine and glycine are essential for human muscle progenitor cell population expansion

2019 ◽  
Author(s):  
Brandon J. Gheller ◽  
Jamie E. Blum ◽  
Erica L. Bender ◽  
Mary E. Gheller ◽  
Esther W. Lim ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acid ◽  
Muscle Regeneration ◽  
Adult Stem Cells ◽  
De Novo ◽  
Population Expansion ◽  
Skeletal Muscle Regeneration ◽  
Dependent Manner ◽  
Older Individuals ◽  
Age Related

SummarySkeletal muscle regeneration is reliant on a population of muscle specific adult stem cells (muscle progenitor cells; MPCs). During regeneration, the MPC population undergoes a transient and rapid period of population expansion, which is necessary to repair damaged myofibers and restore muscle homeostasis. Much research has focused on the age-related accumulation of negative regulators of regeneration, while the age-related decline of nutrient and metabolic determinants of the regenerative process needs examination. We hypothesized that older individuals, a population that is at risk for protein malnutrition, have diminished availability of amino acids that are necessary for MPC function. Here, we identified that levels of the non-essential amino acid serine are reduced in the skeletal muscle of healthy, older individuals. Furthermore, using stable-isotope tracing studies, we demonstrate that primary, human MPCs (hMPCs) exhibit a limited capacity for de novo biosynthesis of serine and the closely related amino acid glycine. We identified that serine and glycine are essential for hMPC proliferation and, therefore, population expansion. Serine and glycine were necessary to support synthesis of the intracellular antioxidant glutathione, and restriction of serine and glycine was sensed in an EIF2α-dependent manner resulting in cell cycle arrest in G0/G1. In conclusion, we elucidate that, despite an absolute requirement of serine/glycine for hMPC proliferation, availability of serine in the skeletal muscle microenvironment is limited to the hMPCs of healthy older adults and is a likely underlying mechanism for impaired skeletal muscle regeneration with advancing age. Graphical Abstract

scholarly journals An economical and highly adaptable optogenetics system for individual and population-level manipulation of Caenorhabditis elegans

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
M. Koopman ◽  
L. Janssen ◽  
E. A. A. Nollen
Keyword(s):  
Caenorhabditis Elegans ◽  
Light Stimulus ◽  
Cholinergic Neurons ◽  
Model Organisms ◽  
Parameter Study ◽  
Multiple Model ◽  
Excitable Cells ◽  
Specific Expression ◽  
C Elegans ◽  
Age Related

Abstract Background Optogenetics allows the experimental manipulation of excitable cells by a light stimulus without the need for technically challenging and invasive procedures. The high degree of spatial, temporal, and intensity control that can be achieved with a light stimulus, combined with cell type-specific expression of light-sensitive ion channels, enables highly specific and precise stimulation of excitable cells. Optogenetic tools have therefore revolutionized the study of neuronal circuits in a number of models, including Caenorhabditis elegans. Despite the existence of several optogenetic systems that allow spatial and temporal photoactivation of light-sensitive actuators in C. elegans, their high costs and low flexibility have limited wide access to optogenetics. Here, we developed an inexpensive, easy-to-build, modular, and adjustable optogenetics device for use on different microscopes and worm trackers, which we called the OptoArm. Results The OptoArm allows for single- and multiple-worm illumination and is adaptable in terms of light intensity, lighting profiles, and light color. We demonstrate OptoArm’s power in a population-based multi-parameter study on the contributions of motor circuit cells to age-related motility decline. We found that individual components of the neuromuscular system display different rates of age-dependent deterioration. The functional decline of cholinergic neurons mirrors motor decline, while GABAergic neurons and muscle cells are relatively age-resilient, suggesting that rate-limiting cells exist and determine neuronal circuit ageing. Conclusion We have assembled an economical, reliable, and highly adaptable optogenetics system which can be deployed to address diverse biological questions. We provide a detailed description of the construction as well as technical and biological validation of our set-up. Importantly, use of the OptoArm is not limited to C. elegans and may benefit studies in multiple model organisms, making optogenetics more accessible to the broader research community.

Effects of Emphysema on Skeletal Muscle Fiber Atrophy in Hamsters

2004 ◽  
Vol 36 (Supplement) ◽  
pp. S332
Author(s):  
John P. Mattson ◽  
Michael D. Delp ◽  
David C. Poole
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fiber ◽  
Skeletal Muscle Fiber ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

The transcription factor ATF4 promotes skeletal muscle fiber atrophy during fasting

2011 ◽  
Vol 25 (S1) ◽  
Author(s):  
Scott Matthew Ebert ◽  
Daniel K Fox ◽  
Kale S Bongers ◽  
Sharon E Malmberg ◽  
Christopher M Adams
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Muscle Fiber ◽  
Skeletal Muscle Fiber ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

scholarly journals Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4

2013 ◽  
Vol 305 (7) ◽  
pp. E907-E915 ◽  
Author(s):  
Kale S. Bongers ◽  
Daniel K. Fox ◽  
Scott M. Ebert ◽  
Steven D. Kunkel ◽  
Michael C. Dyle ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Fiber ◽  
Molecular Mechanisms ◽  
Skeletal Muscle Atrophy ◽  
Muscle Denervation ◽  
Mrna Induction ◽  
Convergence Point ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

Skeletal muscle denervation causes muscle atrophy via complex molecular mechanisms that are not well understood. To better understand these mechanisms, we investigated how muscle denervation increases growth arrest and DNA damage-inducible 45α ( Gadd45a) mRNA in skeletal muscle. Previous studies established that muscle denervation strongly induces Gadd45a mRNA, which increases Gadd45a, a small myonuclear protein that is required for denervation-induced muscle fiber atrophy. However, the mechanism by which denervation increases Gadd45a mRNA remained unknown. Here, we demonstrate that histone deacetylase 4 (HDAC4) mediates induction of Gadd45a mRNA in denervated muscle. Using mouse models, we show that HDAC4 is required for induction of Gadd45a mRNA during muscle denervation. Conversely, forced expression of HDAC4 is sufficient to increase skeletal muscle Gadd45a mRNA in the absence of muscle denervation. Moreover, Gadd45a mediates several downstream effects of HDAC4, including induction of myogenin mRNA, induction of mRNAs encoding the embryonic nicotinic acetylcholine receptor, and, most importantly, skeletal muscle fiber atrophy. Because Gadd45a induction is also a key event in fasting-induced muscle atrophy, we tested whether HDAC4 might also contribute to Gadd45a induction during fasting. Interestingly, however, HDAC4 is not required for fasting-induced Gadd45a expression or muscle atrophy. Furthermore, activating transcription factor 4 (ATF4), which contributes to fasting-induced Gadd45a expression, is not required for denervation-induced Gadd45a expression or muscle atrophy. Collectively, these results identify HDAC4 as an important regulator of Gadd45a in denervation-induced muscle atrophy and elucidate Gadd45a as a convergence point for distinct upstream regulators during muscle denervation and fasting.

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