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Madoka IkemotoUezumi Heying Zhou Tamaki Kurosawa Yuki Yoshimoto Masashi Toyoda Nobuo Kanazawa Tatsu Nakazawa Mitsuhiro Morita Kunihiro Tsuchida Akiyoshi Uezumi 《Aging cell》2022,21(1)
Sarcopenia is an important health problem associated with adverse outcomes. Although the etiology of sarcopenia remains poorly understood, factors apart from muscle fibers, including humoral factors, might be involved. Here, we used cytokine antibody arrays to identify humoral factors involved in sarcopenia and found a significant increase in levels of milk fat globule epidermal growth factor 8 (MFG‐E8) in skeletal muscle of aged mice, compared with young mice. We found that the increase in MFG‐E8 protein at arterial walls and neuromuscular junctions (NMJs) in muscles of aged mice. High levels of MFG‐E8 at NMJs and an age‐related increase in arterial MFG‐E8 have also been identified in human skeletal muscle. In NMJs, MFG‐E8 is localized on the surface of terminal Schwann cells, which are important accessory cells for the maintenance of NMJs. We found that increased MFG‐E8 at NMJs precedes age‐related denervation and is more prominent in sarcopenia‐susceptible fast‐twitch than in sarcopenia‐resistant slow‐twitch muscle. Comparison between fast and slow muscles further revealed that arterial MFG‐E8 can be uncoupled from sarcopenic phenotype. A genetic deficiency in MFG‐E8 attenuated age‐related denervation of NMJs and muscle weakness, providing evidence of a pathogenic role of increased MFG‐E8. Thus, our study revealed a mechanism by which increased MFG‐E8 at NMJs leads to age‐related NMJ degeneration and suggests that targeting MFG‐E8 could be a promising therapeutic approach to prevent sarcopenia. 相似文献
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Corticotropin releasing factor (CRF) dysregulation is implicated in mood and anxiety disorders such as posttraumatic stress disorder (PTSD). CRF is expressed in areas engaged in fear and anxiety processing including the central amygdala (CeA). Complicating our ability to study the contribution of CRF-containing neurons to fear and anxiety behavior is the wide variety of cell types in which CRF is expressed. To manipulate specific subpopulations of CRF containing neurons, our lab has developed a mouse with a Cre recombinase gene driven by a CRF promoter (CRFp3.0Cre) (Martin et al., 2010). In these studies, mice that have the gene that encodes NR1 (Grin1) flanked by loxP sites (floxed) were crossed with our previously developed CRFp3.0Cre mouse to selectively disrupt Grin1 within CRF containing neurons (Cre+/fGrin1+). We find that disruption of Grin1 in CRF neurons did not affect baseline levels of anxiety, locomotion, pain sensitivity or exploration of a novel object. However, baseline expression of Grin1 was decreased in Cre+/fGrin1+ mice as measured by RTPCR. Cre+/fGrin1+ mice showed enhanced auditory fear acquisition and retention without showing any significant effect on fear extinction. We measured Gria1, the gene that encodes AMPAR1 and the CREB activator Creb1 in the amygdala of Cre+/fGrin1+ mice after fear conditioning. Both Gria1 and Creb1 were enhanced in the amygdala after training. To determine if the Grin1-expressing CRF neurons within the CeA are responsible for the enhancement of fear memory in adults, we infused a lentivirus with Cre driven by a CRF promoter (LV pCRF-Cre/fGrin1+) into the CeA of floxed Grin1 mice. Cre driven deletion of Grin1 specifically within CRF expressing cells in the CeA also resulted in enhanced fear memory acquisition and retention. Altogether, these findings suggest that selective disruption of Grin1 within CeA CRF neurons strongly enhances fear memory. 相似文献
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Il-Su Kwon Deuk-Su Park Hyeon-Cheol Shin Myung-Gyu Seok Jae-Keun Oh 《Journal of Exercise Nutrition & Biochemistry》2021,25(3):1
[Purpose]We aimed to identify the effects of marine oligomeric polyphenol (MOP) intake in elderly individuals with sarcopenia.[Methods]Older adults (aged 65 years or older) were recruited based on the diagnostic criterion for sarcopenia and were randomly assigned to the MOP intake group (n=10) or the placebo (PBO) intake group (n=10). To determine the effect of MOP intake received for four weeks, the pre- and post-intake body composition (weight, skeletal muscle mass, and bone density) and senior fitness tests were assessed.[Results]Our results showed there were significant differences in the skeletal muscle mass (p=0.039), bone density (p=0.020), fat-free mass index (p=0.026), and 2.4 m up and go test (p=0.001) between pretest and post-test. There was a significant difference between the pre-test and post-test and an interaction effect for the one-leg stand test (p=0.010 and p=0.049, respectively). However, there were no significant differences in body fat percentage, calf circumference, grip strength, or the chair rise test.[Conclusion]Some variables exhibited significant differences in the pre- and post-assessments, and there was an interaction effect for the one-leg stand. However, this was insufficient to prove the effectiveness of MOP intake in improving sarcopenia. Therefore, additional studies are essential to examine the effects of MOP intake and exercise intervention on the body composition and fitness of patients over a longer period. 相似文献
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Yan Huang Beiling Wu Dingzhu Shen Jiulin Chen Zhihua Yu Chuan Chen 《International journal of biological sciences》2021,17(1):151
As a systemic syndrome characterized by age-associated degenerative skeletal muscle atrophy, sarcopenia leads to a risk of adverse outcomes in the elderly. Age-related iron accumulation is found in the muscles of sarcopenia animal models and patients, but the role of iron in sarcopenia remains poorly understood. It has been recently found that iron overload in several diseases is involved in ferroptosis, an iron- dependent form of programmed cell death. However, whether this excess iron can result in ferroptosis in muscles is still unclear. In our present study, we found that ferric citrate induced ferroptosis in C2C12 cells, as well as impaired their differentiation from myoblasts to myotubes. Due to the decreased muscle mass and fiber size, 40-week-old senescence accelerated mouse prone 8 (SAMP8) mice were used as a sarcopenia model, in whose muscles the iron content and markers of ferroptosis were found to increase, compared to 8-week- old SAMP8 controls. Moreover, our results showed that iron overload upregulated the expression of P53, which subsequently repressed the protein level of Slc7a11 (solute carrier family 7, member 11), a known ferroptosis-related gene. The downregulation of Slc7a11 then induced the ferroptosis of muscle cells through the accumulation of lipid peroxidation products, which may be one of the causes of sarcopenia. The findings in this study indicate that iron plays a key role in triggering P53- Slc7a11-mediated ferroptosis in muscles, and suggest that targeting iron accumulation and ferroptosis might be a therapeutic strategy for treating sarcopenia. 相似文献
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The age-related loss of skeletal muscle mass and function that is associated with sarcopenia can result in ultimate consequences such as decreased quality of life. The causes of sarcopenia are multifactorial and include environmental and biological factors. The purpose of this review is to synthesize what the literature reveals in regards to the cellular regulation of sarcopenia, including impaired muscle regenerative capacity in the aged, and to discuss if physiological stimuli have the potential to slow the loss of myogenic potential that is associated with sarcopenia. In addition, this review article will discuss the effect of aging on Notch and Wnt signaling, and whether physiological stimuli have the ability to restore Notch and Wnt signaling resulting in rejuvenated aged muscle repair. The intention of this summary is to bring awareness to the benefits of consistent physiological stimulus (exercise) to combating sarcopenia as well as proclaiming the usefulness of contraction-induced injury models to studying the effects of local and systemic influences on aged myogenic capability. 相似文献
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Fabio Demontis Rosanna Piccirillo Alfred L. Goldberg Norbert Perrimon 《Disease models & mechanisms》2013,6(6):1339-1352
A characteristic feature of aged humans and other mammals is the debilitating, progressive loss of skeletal muscle function and mass that is known as sarcopenia. Age-related muscle dysfunction occurs to an even greater extent during the relatively short lifespan of the fruit fly Drosophila melanogaster. Studies in model organisms indicate that sarcopenia is driven by a combination of muscle tissue extrinsic and intrinsic factors, and that it fundamentally differs from the rapid atrophy of muscles observed following disuse and fasting. Extrinsic changes in innervation, stem cell function and endocrine regulation of muscle homeostasis contribute to muscle aging. In addition, organelle dysfunction and compromised protein homeostasis are among the primary intrinsic causes. Some of these age-related changes can in turn contribute to the induction of compensatory stress responses that have a protective role during muscle aging. In this Review, we outline how studies in Drosophila and mammalian model organisms can each provide distinct advantages to facilitate the understanding of this complex multifactorial condition and how they can be used to identify suitable therapies. 相似文献
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Francesca Ascenzi Laura Barberi Gabriella Dobrowolny Aline Villa Nova Bacurau Carmine Nicoletti Emanuele Rizzuto Nadia Rosenthal Bianca Maria Scicchitano Antonio Musar 《Aging cell》2019,18(3)
The decline in skeletal muscle mass and strength occurring in aging, referred as sarcopenia, is the result of many factors including an imbalance between protein synthesis and degradation, changes in metabolic/hormonal status, and in circulating levels of inflammatory mediators. Thus, factors that increase muscle mass and promote anabolic pathways might be of therapeutic benefit to counteract sarcopenia. Among these, the insulin‐like growth factor‐1 (IGF‐1) has been implicated in many anabolic pathways in skeletal muscle. IGF‐1 exists in different isoforms that might exert different role in skeletal muscle. Here we study the effects of two full propeptides IGF‐1Ea and IGF‐1Eb in skeletal muscle, with the aim to define whether and through which mechanisms their overexpression impacts muscle aging. We report that only IGF‐1Ea expression promotes a pronounced hypertrophic phenotype in young mice, which is maintained in aged mice. Nevertheless, examination of aged transgenic mice revealed that the local expression of either IGF‐1Ea or IGF‐1Eb transgenes was protective against age‐related loss of muscle mass and force. At molecular level, both isoforms activate the autophagy/lysosome system, normally altered during aging, and increase PGC1‐α expression, modulating mitochondrial function, ROS detoxification, and the basal inflammatory state occurring at old age. Moreover, morphological integrity of neuromuscular junctions was maintained and preserved in both MLC/IGF‐1Ea and MLC/IGF‐1Eb mice during aging. These data suggest that IGF‐1 is a promising therapeutic agent in staving off advancing muscle weakness. 相似文献
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Gilles Gouspillou Isabelle Bourdel‐Marchasson Richard Rouland Guillaume Calmettes Marc Biran Véronique Deschodt‐Arsac Sylvain Miraux Eric Thiaudiere Philippe Pasdois Dominique Detaille Jean‐Michel Franconi Marion Babot Véronique Trézéguet Laurent Arsac Philippe Diolez 《Aging cell》2014,13(1):39-48
With aging, most skeletal muscles undergo a progressive loss of mass and strength, a process termed sarcopenia. Aging‐related defects in mitochondrial energetics have been proposed to be causally involved in sarcopenia. However, changes in muscle mitochondrial oxidative phosphorylation with aging remain a highly controversial issue, creating a pressing need for integrative approaches to determine whether mitochondrial bioenergetics are impaired in aged skeletal muscle. To address this issue, mitochondrial bioenergetics was first investigated in vivo in the gastrocnemius muscle of adult (6 months) and aged (21 months) male Wistar rats by combining a modular control analysis approach with 31P magnetic resonance spectroscopy measurements of energetic metabolites. Using this innovative approach, we revealed that the in vivo responsiveness (‘elasticity’) of mitochondrial oxidative phosphorylation to contraction‐induced increase in ATP demand is significantly reduced in aged skeletal muscle, a reduction especially pronounced under low contractile activities. In line with this in vivo aging‐related defect in mitochondrial energetics, we found that the mitochondrial affinity for ADP is significantly decreased in mitochondria isolated from aged skeletal muscle. Collectively, the results of this study demonstrate that mitochondrial bioenergetics are effectively altered in vivo in aged skeletal muscle and provide a novel cellular basis for this phenomenon. 相似文献
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Huansheng Yang Dezhi Fu Hua Shao Xiangfeng Kong Wence Wang Xiaojian Yang Charles M. Nyachoti Yulong Yin 《PloS one》2012,7(12)
Genetic selection strategies towards increased prolificacy have resulted in more and more increased littler size and incidences of impaired fetal development. Low birth weight (LBW) piglets, with long-term alterations in structure, physiology and metabolism, have lower survival rates and poor growth performance. The aim of the study was to compare the plasma, liver and skeletal muscle contents of neutral amino acids (NAA) and the intestinal expression of NAA transporters between LBW and high birth weight (HBW) suckling Huanjiang mini-piglets. Forty piglets with either LBW or HBW (20 piglets per group) were sampled on day 0, 7, 14 and 21 of age to give 5 observations per day per group. The contents of NAA in plasma, liver and skeletal muscle were measured, and jejunal expression of transporters for NAA, including Slc6a19 (B0AT1) and Slc1a5 (ASCT2), were determined by real-time RT-PCR and Western Blot, respectively. Results showed that the suckling piglets with LBW had higher contents of Thr, Ser, Gly, Ala, Val, Met, Ile, Leu, Tyr, Phe and Pro in liver, and Gly in skeletal muscle, whereas lower contents of Met, Ser and Ala in plasma when compared with the HBW littermates. Consistent with the content differences in plasma NAA, the jejunal expression profiles of both Slc6a19 (B0AT1) and Slc1a5 (ASCT2) in the LBW piglets were lower in compared with the HBW littermates during the early suckling period. These findings suggested that intestinal dysfunction in the LBW piglets may be one of the reasons in altered physiology and metabolism states of other organs, which result in lower survival and growth rate. 相似文献
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Jabbar Khan Sanaullah Khan Sobia Attaullah Ijaz Ali Shahid Niaz Khan 《BMC cell biology》2012,13(1):1-9
Background
Autophagy is a ubiquitous cellular process responsible for the bulk degradation of cytoplasmic components through the autophagosomal-lysosomal pathway. In skeletal muscle, autophagy has been regarded as a key regulator for muscle mass maintenance, and its imbalance leads to sarcopenia. However, the underlying mechanism is poorly understood.Results
In this study, we demonstrate that ceMTM3, a FYVE-domain containing myotubalarin family phosphatase, is required for the maintenance of muscle fibers by preventing excessive autophagy in Caenorhabditis elegans. Knockdown of ceMTM3 by using feeding-based RNA interference caused loss of muscle fibers accompanied by shortening of muscle cell and body size in aged C. elegans worms. This was preceded by the occurrence of excessive autophagy in the muscle and other tissues, which subsequently resulted in increased lysosomal activity and necrotic cell death. However, knockdown of ceMTM3 did not aggravate the abnormalities of muscle wasting in autophagy-deficient atg-18 mutant worms.Conclusions
Our data suggest an important role of ceMTM3 in regulating autophagy and maintaining muscle fibers. This study may have clinical implications for prevention and treatment of sarcopenia. 相似文献17.
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Sang Ouk Chin Sang Youl Rhee Suk Chon You-Cheol Hwang In-Kyung Jeong Seungjoon Oh Kyu Jeung Ahn Ho Yeon Chung Jeong-taek Woo Sung-Woon Kim Jin-Woo Kim Young Seol Kim Hong-Yup Ahn 《PloS one》2013,8(3)
Background
The association between sarcopenia and cardiovascular disease (CVD) in elderly people has not been adequately assessed. The aim of this study was to investigate whether CVD is more prevalent in subjects with sarcopenia independent of other well-established cardiovascular risk factors in older Korean adults.Method
This study utilized the representative Korean population data from the Korea National Health and Nutrition Examination Survey (KNHANES) which was conducted in 2009. Subjects older than 65 years of age with appendicular skeletal muscle mass (ASM) determined by dual energy X-ray absorptiometry were selected. The prevalence of sarcopenia in the older Korean adults was investigated, and it was determined whether sarcopenia is associated with CVD independent of other well-known risk factors.Results
1,578 subjects aged 65 years and older with the data for ASM were selected, and the overall prevalence of sarcopenia was 30.3% in men and 29.3% in women. Most of the risk factors for CVD such as age, waist circumference, body mass index, fasting plasma glucose and total cholesterol showed significant negative correlations with the ratio between appendicular skeletal muscle mass and body weight. Multiple logistic regression analysis demonstrated that sarcopenia was associated with CVD independent of other well-documented risk factors, renal function and medications (OR, 1.768; 95% CI, 1.075–2.909, P = 0.025).Conclusions
Sarcopenia was associated with the presence of CVD independent of other cardiovascular risk factors after adjusting renal function and medications. 相似文献20.
Normal aging in humans is associated with progressive decrease in skeletal muscle mass and strength (sarcopenia) which contributes to frailty and falls. The age associated changes in body composition result from lower levels of anabolic hormones, oxidative damage, neuromuscular alterations and a general decrease in muscle protein turnover. In this review we discuss the potential mechanisms and physical activity as prevention and treatment of sarcopenia. 相似文献