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Mrtabolism is dependent on a well-orchestrated myogenic program that includes the activation of muscle-specific stem cells MuSCs and expansion of MuSCs and their committed progeny, the muscle Rehuvenates cells MPCs Figure 1A. Liver detoxification for mental clarity and MPCs will collectively metabooism referred to as MPCs throughout, except where cell specificity is necessary.
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Merabolism 1. Simplified schematic of the Rejuvenatex process A metaboism timing Meabolism metabolic pathways B. Color corresponds to relative pathway use; Rejuvenats color indicates meyabolism intense relative metaboliam use.
Comparisons mftabolism made within each bar, not between bars. ECAR, Extracellular acidification rate; OCR, Oxygen consumption rate; FAO, Fatty acid oxidation; Anti-cancer awareness and education, paired box metaboljsm MyoD, Metabolims determination protein 1; MyoG, Myogenin.
Studies in rodents identified that MPC depletion severely impairs the muscle regeneration process, following an acute injury Sambasivan et al. Additionally, MPCs are essential to prevent tissue fibrosis. Following synergist ablation surgery in mice, MPC depletion caused an increase in extracellular matrix deposition and expansion of the fibroblast cell population Fry et al.
Follow-up studies revealed that MPCs secrete exosomes containing microRNAs specifically miRthat can attenuate collagen biosynthesis and secretion from nearby fibroblasts Fry et al. Thus, in response to an acute injury, robust MPC activation is required to restore muscle mass and prevent fibrosis.
For example, freshly isolated MPCs are used as model of activation. Growth media is used to promote the proliferation of MPCs. Serum withdraw i. Duration of MPC differentiation is associated with myotube formation.
For example, the first day in differentiation media little to no fusion of cells is observed. However, with extended duration in differentiation media, there is an increase in the number of fused cells representing myotube formation. In vitro systems have been used extensively for examining nutrient and metabolic determinants of myogenesis, as detailed in the following sections.
Impaired skeletal muscle regeneration is commonly observed with advancing age, and in individuals with metabolic conditions including obesity, type two diabetes, and chronic kidney disease Chakravarthy et al. This impaired capacity for muscle regeneration leads to pathological tissue remodeling.
Specifically, older animals or animals with obesity and insulin resistance show increased fibrotic tissue deposition and intramuscular fat deposition after injury Brack et al. Adipose and fibrotic tissue do not perform the same essential functions as skeletal muscle i.
Impaired muscle regeneration, as observed in aging and chronic disease, is driven by a combination of changes in intracellular factors and cell-extrinsic factors.
Key intracellular factors shown to be altered in conditions of impaired muscle regeneration include oxidative stress, inflammatory signaling, signal transduction, and altered metabolism Aragno et al. While many therapies for improving muscle function after injury, in individuals with impairment have been proposed, as reviewed elsewhere Baoge et al.
However, despite some promising results, these therapies are not yet clinically available. Identifying novel regulators of MPC function may provide new strategies to augment proposed therapies. All cells, including muscle stem cells, require conversion of nutrients to energy and biosynthetic intermediates to support maintenance and cell division.
Glycolysis, the breakdown of glucose into pyruvate, and the TCA cycle, a coordinated set of enzymatic reactions that convert acetyl-coA to carbon dioxide, are key energy generating pathways within cells Figure 2.
Acetyl-coA can be derived from pyruvate, lactate, acetate, or catabolism of fatty acids and certain amino acids leucine, lysine, phenylalanine, tryptophan, and tyrosine.
Additionally, glutamine, and other amino acids asparagine, aspartate, valine, methionine, threonine, proline, arginine, histidine feed the TCA cycle at entry points other than acetyl-coA.
Both glycolysis and the TCA cycle generate NADH. Figure 2. Energy generating pathways and key protein in MPCs. PKM2, Pyruvate kinase M2; PDH, pyruvate dehydrogenase; ACLY, ATP Citrate Lyase. In addition to energy generation, glycolysis and the TCA cycle support synthesis of biosynthetic intermediates Figure 2.
Glucosephosphate, the first intermediate of glycolysis is a substrate for the pentose phosphate pathway, a series of reactions that produce nucleotides, and NADPH, an essential cofactor for fatty acid synthesis and oxidative stress management.
Fructosephosphate, the next glycolytic intermediate is a precursor for the hexosamine pathway, which generates UDP-GlcNAc, a substrate that glycosylates proteins. Glycolytic intermediates provide a glycerol backbone for triacylglyceride synthesis, and also feed the serine biosynthetic pathway, which generates serine and glycine.
Pyruvate, the final glycolytic intermediate can be transaminated to alanine. Intermediates of the TCA cycle are substrates for synthesis of fatty acids and sterols, nutritionally, non-essential amino acids NEAAspurines, and heme.
Importantly, as intermediates in the TCA cycle are used for biosynthetic pathways, these intermediates can be replenished through anaplerotic reactions. In the following sections we will review changes in relative occurrence of glycolytic and oxidative metabolism during myogenesis.
Important to note, while these processes can be compared across the myogenic stages, the glycolytic and oxidative pathways are not mutually exclusive. Next, we will review knowledge about essentiality and function of glycolytic and oxidative metabolism, which will be combined since they are inherently linked.
Following, we will briefly discuss alteration in metabolism in MPCs from populations with impaired regeneration, and then review metabolic proteins that contribute to coordination of cellular metabolism. Lastly, we will discuss historical and recent advances in understanding the role of circulating nutrients in MPC function.
Studies have examined changes in energy generating pathways that occur throughout the myogenic process Figure 1B. Extracellular acidification rate ECARa proxy measurement for glycolysis, is increased in freshly isolated MPCs a model of activation and proliferating MPCs compared to quiescent MPCs Ryall et al.
In proliferating human MPCs, mRNA levels of the glucose transporters GLUT1 and GLUT4 did not differ between an early and later timepoint of proliferation Riddle et al.
ECAR returns to levels observed in quiescent MPCs during MPC differentiation, in primary mouse MPCs isolated from injured mice Pala et al. Similarly, in cultured primary mouse MPCs, ECAR levels are lower in differentiating, compared to proliferating, MPCs Yucel et al.
Thus, maximum ECAR occurs during MPC proliferation. Similar to glycolytic metabolism, oxidative metabolism is dynamic during myogenesis. Oxygen consumption rate OCRa measurement of mitochondrial respiration, is unaltered between quiescent and freshly isolated MPCs Ryall et al. Interestingly, despite no change in OCR during the transition from quiescence to activation, activation is associated with an increase in mitochondrial content and expression of genes that coordinate TCA cycle activity, which may indicate increases in mitochondrial capacity precede increases in oxidative metabolism Ryall et al.
This was confirmed by a second study that showed the transition from quiescence to activation is associated with increased mitochondrial content, both in MPCs at the site of injury and in MPCs in distant muscles that also were activated by the injury Rodgers et al.
In proliferating MPCs, OCR is upregulated compared to quiescent MPCs and mitochondrial content and membrane potential remain elevated Pala et al.
Taken together, evidence suggests an increase in mitochondrial content during MPC activation that leads to increased OCR during MPC proliferation.
Oxidative metabolism is also dynamic during differentiation and myotube formation. OCR, mitochondrial content, and mitochondrial membrane potential remain elevated during MPC differentiation 5 days post-injury compared to quiescent levels in MPCs isolated from injured mice Pala et al.
In immortalized MPCs, OCR is higher in MPCs that are differentiated for 6 days, a time when myotube formation is prevalent, compared to proliferating MPCs. Conversely, cultured primary mouse MPCs showed decreased OCR and reduced mitochondrial content in MPCs that had differentiated for 24 h compared to proliferating MPCs Das et al.
Thus, it is possible that early differentiation is associated with a dip in OCR and mitochondrial content, which is recovered and perhaps magnified at later stages of differentiation. In conjunction with elevated OCR, MPC differentiation is associated with increased fatty acid oxidation FAO.
In cultured primary mouse MPCs, only differentiated MPCs not proliferating show increased OCR in response to palmitate treatment, suggesting that differentiating MPCs may use more FAO compared to proliferating MPCs Sin et al.
Though interestingly, in MPCs isolated from injured mice, transcript levels of genes involved in mitochondrial and peroxisomal FAO are elevated in both proliferating and differentiating MPCs compared to quiescent MPCs Pala et al. Thus, increases in mRNA levels of genes involved in FAO may precede increased reliance on FAO pathways.
Consistent with an increase in energy demand, ATP levels were increased in both proliferating and differentiating MPCs compared to quiescent MPCs Pala et al.
Mitochondrial morphology is also dynamic during the myogenic process. In immortalized MPCs, dynamin 1 like DNM1La protein involved in mitochondrial fission, shows peak expression at 1 day differentiation compared to proliferating MPCs or MPCs differentiated for 3 or 6 days Sin et al.
: Rejuvenates metabolism| DMG Health - Metabolic Rejuvenation Program | Subsequently, we aimed to investigate how prolonged inhibition of glycolysis would interfere with blastema organization and with de novo OB formation Figure 6A. Skeletal muscle wasting occurs in metabolic disorders such as Pompe disease or may arise as a consequence of other factors that lead to altered metabolism in muscle. Non-passaged muscle precursor cells from month old rat skeletal muscle have delayed proliferation and differentiation. GFP line profiles were calculated and summed in height and the intensity center of mass was found in each segment analyzed. Common markers for aging and reproduction were features that appear both in the list of aging biomarkers and in the list of reproduction biomarkers, and were also consistent with molting slowing down aging and improving performance. Accepted : 12 March |
| Access options | Hyperbaric oxygen increases satellite cell proliferation and differentiation while also facilitating macrophage invasion in damaged tissue which may explain the improvements in muscle regeneration and function observed after its use in rats [ 81 ]. Hyperbaric oxygen therapy also promotes muscle repair after injury by stimulating angiogenesis [ 82 ]. It is not clear if hyperbaric oxygen therapy can improve outcomes for chronic diseases. Mesenchymal stem cell therapies are increasing in popularity and generally regulate inflammatory environments by secreting cytokines. In accord with known anti-inflammatory properties, intramuscular injection of mesenchymal stem cells reduces cytokine levels in septic mice [ 64 ]. Additionally transplanted mesenchymal stem cells improve muscle regeneration and restore mitochondrial activity in satellite cells of septic mice [ 64 ]. Intraperitoneal injections of bone marrow derived mesenchymal stem cells improves the morphology of myofibers, increase satellite cell quantity, and improves lifespan overall for Duchenne muscular dystrophy mice [ 84 ]. Two growth factors secreted by mesenchymal stem cells, CXCL12 and osteopontin, facilitate improved regeneration in dystrophic mice [ 84 ]. Despite a growing list of promising basic and preclinical mesenchymal stem cell studies, key obstacles remain. For example, stem cell-based therapies are challenging to standardize and repeated injections of a bulky and dynamic cellular product is not always favorable. Alternatively, injecting exosomes from mesenchymal stem cells may be an option. Indeed, intramuscular exosome treatment reportedly promotes angiogenesis, myogenesis, and muscle regeneration [ 85 ]. In general, satellite cells are often overlooked when evaluating disease associated muscle wasting which may hamper our understanding of this syndrome. One limitation of many studies that assess metabolic dysfunction and wasting of muscle includes the focus on a single muscle, typically the tibialis anterior a hind limb muscle , and neglect of other skeletal muscle types. Another barrier is the multitude of models designed to recapitulate the multifactorial muscle wasting syndrome hampers our ability to elucidate the causes particularly related to altered metabolism and effective treatments. This descriptive review outlines various metabolic abnormalities in satellite cells that are associated with wasting of skeletal muscle; due to the significance of metabolic regulation in satellite cell function our work is a start to interrogating how these metabolic disruptions may be enhancing refractory muscle wasting. There are options available to treat metabolic abnormalities in satellite cells and skeletal disease as detailed in this work. 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The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database Oxford , baw Xie, X. Raj, A. Imaging individual mRNA molecules using multiple singly labeled probes. Methods 5 , — Mueller, F. FISH-quant: automatic counting of transcripts in 3D FISH images. Methods 10 , — Download references. We thank J. Rodgers, L. Liu and Z. De Miguel for intellectual support, and M. Wagner and I. Akimenko for technical assistance. This work was supported by funding from the Stanford University School of Medicine Medical Scientist Training Program T32 GM and CIRM Scholar Training Program TG2 to J. and T. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. Jamie O. Brett, Marina Arjona, Mika Ikeda, Marco Quarta, Antoine de Morrée, Ingrid M. Egner, Luiz A. Perandini, Heather D. Ishak, Armon Goshayeshi, Daniel I. Benjamin, Pieter Both, Cristina Rodríguez-Mateo, Michael J. Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA. Brett, Marina Arjona, Mika Ikeda, Marco Quarta, Antoine de Morrée, Heather D. Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University School of Medicine, Stanford, CA, USA. Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA. Department of Biosciences, University of Oslo, Oslo, Norway. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Neurosciences Interdepartmental Graduate Program, Stanford University School of Medicine, Stanford, CA, USA. Neurology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. You can also search for this author in PubMed Google Scholar. designed experiments. conducted and analysed experiments. wrote the manuscript. Correspondence to Thomas A. a , Non-strenuous voluntary exercise by wheel running in mice. Young or old mice are provided access to a freely rotating wheel or to a locked wheel as a control. Three weeks later, muscles are either assayed with MuSCs in their quiescent state, without injury or MuSC isolation, or assayed for MuSC exit from quiescence, induced by experimental injury or MuSC isolation into culture. MuSCs were FACS-isolated and immediately fixed for EdU staining. c , FACS-isolated MuSCs were assayed for cell size based on forward scatter in flow cytometry. For comparison, also shown are results from young muscles injured three days prior to analysis. d , FACS-isolated MuSCs were assayed for RNA content based on Pyronin Y intensity in flow cytometry. e , FACS-isolated MuSCs were assayed for MyoD expression based on immunocytochemistry. f-h , TA muscles were sectioned and assayed for MyoD-expressing cells f , Kiexpressing cells g , and Pax7-expressing cells h by immunohistochemistry. Representative images quantified in j are shown. Scale bar in l , μm. a — d , Exercise and muscle injury were performed as in Fig. After either four days a , five days b or twenty-eight days c-d , muscles were isolated and stained to examine regeneration. e , Gating strategy for FACS isolation of MuSCs, following a published protocol 45 , i , FACS-isolated MuSCs were cultured for one day and then stained with 7AAD to determine viability by flow cytometry. Scale bar in e , 50 μm. a , Mice were given no access or free access to a running wheel, followed by wheel removal for zero, one, or two weeks. The onset of exercise was staggered so that MuSC isolation was performed at the same time for all groups. a , Old recipient mice that had never exercised received three consecutive daily tail-vein injections with serum collected from old non-exercising or exercising mice. MuSCs were isolated from recipient mice one day after the last injection. a , RT-qPCR in MuSCs from mice independent of those used in the RNA-Seq experiment. C t values were normalized first to the mean of Gapdh , Hprt , and Actb1 and then to the mean Y -Ex level in each experiment, with Y -Ex shown as a dotted line at relative expression 1. b , GSEA results for the Hallmark gene sets in comparisons of RNA-Seq profiles for O -Ex vs. Y -Ex MuSCs. O -Ex NES. d , Single-cell RT-qPCR for Ccnd1 in freshly isolated MuSCs. For comparison, also shown are results for young MuSCs isolated three days after injury. The pairs on each chip were O -Ex vs. Data are summarized with mean and s. NES, normalized enrichment score in b , c ; ES, running enrichment score; S2N, GSEA Signal2Noise ranking metric in c. HET and WT vs. KO n values represent individual mice. b , TA muscles were isolated from twelve-month-old mice that had received tamoxifen injections at three months of age. Muscle sections were stained for Pax7 to identify MuSCs, YFP to identify recombined cells, and laminin to delimit muscle fibers and MuSCs from the interstitium. d , To confirm maintenance of ex vivo quiescence by TubA, MuSCs were kept in culture for three days either in quiescence with TubA or during activation with DMSO vehicle in the continuous presence of EdU and then fixed for analysis. MuSCs were then released for two days in the presence of EdU by removing TubA. e , MuSCs were infected as in Fig. Each lane represents a pool of three to six mice split into the two infection conditions. f , MuSCs infected as in Fig. Source data. a , GSEA results for the Hallmark gene sets in comparisons of RNA-Seq profiles for Y HET vs. Y WT MuSCs. Gene sets are in ascending order based on the mean NES. NES, normalized enrichment score in a , b ; ES, running enrichment score; S2N, GSEA Signal2Noise ranking metric in b. a , For each gene in the RNA-Seq datasets, a weighted correlation coefficient against Ccnd1 was calculated across all samples. Shown are examples of negative, zero, and positive correlations, in which expression is plotted in log scale and point size conveys sample weight. b , GSEA results for the Hallmark gene sets using the Ccnd1 correlation coefficient of each gene across all samples. Gene sets are in ascending order based on NES. c , GSEA results for TFT gene sets obtained from the Harmonizome database that are experimentally determined TRANSFAC and ChEA and computationally predicted MSigDB and MotifMap. Shown are the top twelve anticorrelated gene sets based on NES for each gene set collection total gene sets screened: 72 for TRANSFAC, 74 for ChEA, for MSigDB, and 34 for MotifMap. Smad3 is highlighted in each collection. d , Enrichment plots for the Hallmark gene set TGF BETA in each of the previously mentioned RNA-Seq comparisons. NES, normalized enrichment score in b - d ; ES, running enrichment score; S2N, GSEA Signal2Noise ranking metric in d. a-c , Western blots on freshly isolated MuSCs to assess for activating C-terminal phosphorylation of Smad3. a , MuSCs were from Y Veh , O Veh , and O LY mice. Shown is a representative blot and quantification of two blots. b , MuSCs were from WT Veh , HET Veh , and HET LY mice. c , MuSCs were from WT Veh , KO Veh , and KO LY mice. Reprints and permissions. Brett, J. Exercise rejuvenates quiescent skeletal muscle stem cells in old mice through restoration of Cyclin D1. Nat Metab 2 , — Download citation. Received : 05 February Accepted : 12 March Published : 13 April Issue Date : April Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. nature nature metabolism letters article. Subjects Ageing Muscle stem cells Skeletal muscle. Abstract Ageing impairs tissue repair. Access through your institution. Buy or subscribe. Change institution. Learn more. Data availability The data that support the findings of this study are available from the corresponding author upon request. References Sherwin, C. Article CAS PubMed Google Scholar van Praag, H. Article CAS PubMed PubMed Central Google Scholar Abreu, P. Article CAS PubMed Google Scholar Kurosaka, M. Article CAS Google Scholar Dungan, C. Article CAS PubMed PubMed Central Google Scholar Egner, I. Article CAS PubMed Google Scholar Kadi, F. Article CAS PubMed Google Scholar Begue, G. Article CAS PubMed PubMed Central Google Scholar Fujimaki, S. Article CAS PubMed PubMed Central Google Scholar Conboy, I. Article CAS PubMed Google Scholar Cosgrove, B. Article CAS PubMed PubMed Central Google Scholar Price, F. Article CAS PubMed PubMed Central Google Scholar Nishijo, K. Article CAS PubMed PubMed Central Google Scholar Schultz, E. Article CAS PubMed Google Scholar Conboy, I. Article CAS PubMed Google Scholar Rao, S. Article CAS PubMed Google Scholar Skapek, S. 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| What is metabolism? | Metagolism CAS PubMed Responsible alcohol habits Central Rejuvenates metabolism Scholar Dupuis L, Oudart H, Rene F, Gonzalez metaboolism Rejuvenates metabolism JL, Loeffler Rejubenates. Hyaluronan upregulates Ginseng for energy biogenesis and Rejuvenates metabolism adenoside triphosphate production for efficient mitochondrial function in slow-proliferating human mesenchymal stem cells. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. A mass tolerance of 5 ppm and a retention time window tolerance of 10 s were used. Genes Basel. The Muscle Metabolome Differs between Healthy and Frail Older Adults. |
| It’s not your age that’s slowing your metabolism, new research says. Here’s what to do | CNN | Rejuvebates caloric restriction appears Rejuvenates metabolism be Glucagon role in Rejuvenaets Rejuvenates metabolism of myogenesis, metqbolism evidence varies with sex and Responsible alcohol habits Non-dairy milk and therefore requires further investigation [ 79 ]. Our food Rejuvenates metabolism drinks are broken down and converted into energy through complex chemical processes. Thus, mature OB and joint-associated progenitors may act as complementary sources that supply the pre-OB pool. In mice models of ear and digit injuries, regeneration is impaired by OXPHOS inhibition, suggesting that in this context OXPHOS is required to mediate regeneration Shyh-Chang et al. Blau, H. Stem Cells Dev. |
Rejuvenates metabolism -
Our metabolism is affected by: Age — Metabolism slows down as we get older due to the drop in muscle tissue, neurological and hormonal changes. Body size — A body with more muscle mass and is typically larger than average will have a higher metabolic rate. Fat cells are the slowest burners of kilojoules.
Coffee — an espresso after a meal is a great way to boost digestion and metabolism Deficiencies in diet — such as a lack of iodine, can lower metabolic rate. Environmental temperature — Whether too hot or cold, if our body has to work harder to maintain body temperature, our metabolic rate will increase.
Genetic predisposition — Our genes may play a role in metabolism. Gender — Typically, males will have a faster metabolic rate, likely due to a higher muscle mass. Hormones — As usual, our hormones have a role to play, with imbalances influencing metabolism.
Illness — Like environmental factors, metabolism has to increase to build an immune response to infection or illness and build new tissues. Muscle mass — As already stated, muscle rapidly burns kilojoules, so the more we have, the better our metabolism will perform.
Physical activity — Exercising regularly builds muscle mass and encourages calorie burn, even during rest periods. What foods supercharge metabolism? What exercises increase metabolism? What supplements increase metabolism?
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What are the best and worst foods for stress? S10 — S Since culture expansion of hMSCs induces a metabolic reconfiguration of central metabolism, the redox cycle balance may also be affected. Sirt-1 regulates mitochondrial biogenesis via PGC-1α and TFAM, which were found to be downregulated in hMSCs at P12 compared to cells at P5.
In addition, the gene expression of PARP1, FOXO1 , and FOXO3 , which are involved in oxidative stress and regulated by Sirt-1 and Sirt-3, was increased in cells of P12 compared to cells at P5 Fig. Western blot results confirm the decrease of Sirt-1, Sirt-3, as well as PGC-1 from P5 to P12 at the protein level Fig.
c Immunocytochemistry of Sirt-1 expression in culture-expanded hMSCs. d Sirt-1 and e Sirt-3 protein levels characterized by flow cytometry.
MFI mean fluorescence intensity. f mRNA levels of Sirt-1 and Sirt-3 in hMSCs. g Genes in DNA repair and mitochondria PARP1, PGC1 , and TFAM regulated by Sirt-1 in hMSCs at different passages. h FOXO pathways FOXO1 and FOXO3 regulated by Sirt-1 and Sirt-3, determined by RT-PCR.
i Sirt-1, Sirt-3, and PGC-1α protein levels during culture expansion of hMSCs determined by Western blot. Western blot analysis confirmed the increase of NAMPT, CD38, and CD73 in senescent hMSCs Fig.
b NAMPT, c CD38, and d CD73 protein expressions were all increased in late passage of hMSCs determined by flow cytometry.
NG negative control. e , f Western blot confirmed the increase of NAMPT, CD38, and CD73 in late passage of hMSCs. NS not statistically significant. Sirt-1 and Sirt-3 expression was also increased Fig. More importantly, senescence was reduced as indicated by reduced SA-β-gal activity in P12 hMSCs Fig.
Correspondingly, colony-forming ability was recovered after short-term NAM treatment from 3 to 11 colonies Fig. After adding NAM, the increase of cell population in the S phase of cell cycle was observed Supplementary Fig.
Consequently, no significant change of population doubling time was announced data not shown. In addition, the presence of NAM increased glycolytic ATP ratio in P12 cells Fig. Consistent with this, P12 hMSCs with NAM treatment was found to exhibit increased basal autophagy level Fig.
The mitophagy was also improved Fig. These improvements lead to the partial recovery from replicative senescence in hMSCs at high passage, as well as the improved mitochondrial fitness that facilitates central energy metabolism.
a NAD level was increased and NADH level was decreased. c Sirt-1 and Sirt-3 expressions were both increased. d SA-β-gal activity was decreased.
e Colony-forming ability CFU-F and f glycolytic ATP ratio were also increased. g Basal autophagy was restored in senescent hMSCs after NAM treatment.
Mitochondrial fitness was restored. h Mitochondrial mass was decreased. i Mitochondrial transmembrane potential MMP and j electron transport chain complex I ETC-I activity was increased. k Mitophagy ability was restored. FCCP mitochondrial uncoupler carbonilcyanide p-triflouromethoxyphenylhydrazone.
l Total reactive oxygen species ROS level was reduced as determined by flow cytometry. Since hMSCs exhibit significant changes induced by replicative expansion, similar analysis was then performed for human dermal fibroblasts hFBs , which were chosen as a representative type of mature adult cells.
In contrast to hMSCs, extensive culture expansion up to passage 15 of hFBs showed no significant difference in population doubling time Fig. Cellular homeostasis was also maintained because no change in autophagic flux was observed Fig.
hFBs at P15 had similar levels of mitochondrial activity and fitness compared to P4 cells, such as mitochondrial mass Fig. No significant changes were found in Sirt-1 and Sirt-3 expression during the expansion of hFBs as well Fig.
Finally, the expression levels of NAMPT, CD38, and CD73 were comparable throughout the expansion process Fig. Together, these data indicate that hFBs do not exhibit replicative senescence and are able to preserve cellular homeostasis in artificial culture environment.
a Population doubling time of hFBs at early and late passage. b SA-β-gal activity for culture-expanded hFBs. c No significant difference for autophagic flux in P4 and P15 hFBs. Red line: negative control. Orange line and blue line represents basal autophagy and with autophagy inhibitor Bafliomycin-A Baf-A , respectively.
d Mitochondrial mass and e mitochondrial transmembrane potential MMP showed no difference for P4 and P15 hFBs. f Mitophagy also showed no significant difference in hFBs during culture expansion.
Orange line and blue line represents untreated and with mitochondrial uncoupler FCCP treatment, respectively. h Sirt-1 and i Sirt-3 protein expression determined by flow cytometry. Beyond multi-lineage differentiation, hMSCs exhibit paracrine and immunomodulatory abilities that facilitate endogenous tissue regeneration, thus are recognized as a potential therapeutic candidate.
For clinical purpose, in vitro large-scale expansion of hMSCs is a necessary step to meet the requirement for cell number and dosages while maintaining genetic stability and therapeutic efficacy 1.
However, progressive loss of stem cell properties and genetic alterations during in vitro culture of hMSCs have been widely reported 1 , This study provides full characterizations of hMSCs during in vitro culture expansion and a novel mechanism underlines replicative senescence, proposing a potential rejuvenation strategy.
In vitro culture conditions have been shown to significantly impact cell properties. For hMSCs, a similar Hayflick limit was observed in our studies and by other groups, with altered morphology and arrested cell proliferation following extensive culture 33 , 34 , 35 , 36 , In fact, ultra-structure study of cellular organelles revealed endoplasmic reticulum and matrix vesicles were also dysregulated after replicative expansion Some reports describe a lower ability for differentiation and decreased multipotency of senescent hMSCs.
For example, some studies showed increased osteogenesis and decreased adipogenesis, while others showed well-preserved adipogenic potential with diminished osteogenic differentiation 33 , 34 , 39 , as observed in our study Supplementary Fig.
This may be due to the different medium compositions but still revealed the disruption of multipotency of hMSCs after extensive expansion. In our study, cell cycle arrest in senescent hMSCs was announced by the gradual increase of p53, p21, and p15 gene expression.
Loss of autophagy has been attributed to functional decline of aged stem cells: for example, aged muscle stem cells and hematopoietic stem cells showed the impaired autophagy along with loss of their regenerative potential, both in vitro and in vivo 43 , Restoring autophagy via rapamycin and spermidine treatment partially restored stem cell functions in vivo 43 , An interesting phenomenon is that the heterogeneity of aged stem cells also leads to differential autophagic activity 44 , potentially explaining the reduced autophagy in hMSCs during culture expansion as heterogeneity increases For the first time, our results demonstrate a close link between gradual loss of basal autophagy and mitophagy , a hallmark of cellular homeostasis 46 , 47 , and the replicative senescence in hMSCs.
Our previous studies have extensively demonstrated the metabolic plasticity of hMSCs under artificial culture conditions 15 , 16 , 48 , Upon removal from the in vivo niche, hMSCs start to adapt to the in vitro environment by utilizing both glycolysis and OXPHOS for ATP production.
Cellular homeostasis that contributes to pluripotency and clonal phenotype is well maintained by the low level of glycolytic metabolism for stem cells 15 , As metabolism shifts from glycolysis towards primarily OXPHOS, a breakdown of cellular homeostasis is expected due to the accumulation of ROS and damaged organelles.
Thus, the metabolic state could also act as a hallmark of replicative senescence during hMSC expansion. As shown in this study, both OCR and ECAR were increased during culture expansion of hMSCs, contributing to the slightly increased ATP production. However, the ratio of ATP generated from glycolysis gradually decreased, indicating that hMSCs switch their metabolism toward OXPHOS and other pathways to efficiently produce more ATP in order to support extensive replication and maintain stem cell properties This process may exhaust mitochondrial functions and generate ROS and damaged organelles as autophagy is impaired in senescent hMSCs Proteomics and metabolomics analysis in current study also reveal the metabolic dysregulations in hMSCs following culture expansion, such as the upregulated fatty acid β-oxidation in late passage hMSCs.
This observation may explain the slight increase of ATP production during culture expansion of hMSCs, with gradually decreased percentage of glycolytic ATP.
Clearly, hMSCs with extensive culture exhibit metabolic imbalance, which is a hallmark of loss of homeostasis. Moreover, genomics analysis of hMSCs with replicative senescence has demonstrated that genes involved in cell differentiation and apoptosis are upregulated in senescent cells, whereas genes involved in mitosis and proliferation are downregulated Global omics analysis provides the evidence that changes in replicative senescence may be a general property across hMSC lines regardless of tissue source and culture conditions, but more investigations of the universality of the hMSC replicative senescence in response to extensive culture are still needed 52 , As a redox cofactor, NAD plays a central role in energy metabolism and also acts as a substrate for enzymes involved in cellular signaling pathways, such as PARPs and Sirtuins Interestingly, our study did not observe significant change in AMPK activity, an energy gauge for sensing energetic alteration.
Thus, culture-induced replicative senescence of hMSCs may differ from in vivo stem cell aging in the context of energy production. Notably, decreased ETC activity generally leads to decreased OCR, which is opposite in our observations.
This may be due to other cellular events also regulating basal OCR, such as ATP turnover, proton leak, and non-mitochondrial oxygen consumption ROS formation Similar to the way that CD38 is upregulated in immune cells under inflammatory environment, hMSC senescence can be attributed to chorionic inflammation following in vitro culture 69 , This study further examined whether human dermal fibroblasts exhibit similar changes during culture expansion.
Surprisingly, within a similar number of population doublings, hFBs exhibit a relatively consistent cell growth and β-gal activity, indicating that the cellular senescence did not increase following the expansion of hFBs. These results demonstrate that hMSCs and hFBs have different sensitivities to artificial culture environment under in vitro expansion.
Generally, fibroblasts were considered to share similar phenotypic characteristics with MSCs 32 , 71 , 72 , including lineage-specific differentiation and colony-forming ability, though these properties are highly donor- and tissue source-dependent 71 , Studies have revealed that fibroblasts can be cultured for 60—80 population doublings before entering replicative senescence 74 , making them much more replicative compared to hMSCs.
Moreover, hFBs do not exhibit metabolic reconfiguration under the nutrient-enriched culture environment. In fact, switching to anaerobic metabolism mostly occurs in response to serum starvation rather than reducing oxygen level in hFB culture By comparison, hMSCs are extremely sensitive to their culture environment including nutrients, oxidative stress, mechanical stimuli, or even gravity hMSCs are able to adapt to different culture environments and stimuli e.
The adaption process, in most cases, is required for engineering hMSCs with enhanced therapeutic potentials In fact, this sensitivity provides the possibility to engineer hMSCs with culture conditions instead of genetic modification.
For instance, hypoxia, 3D aggregation, and cytokine priming can enhance hMSC properties for clinical purposes via metabolic reconfiguration 15 , 49 , 78 , 79 , hFBs, however, may not be engineered by the metabolic preconditioning since they are less sensitive to the artificial culture environment.
In addition, mitochondrial damage and loss of autophagy also contribute to the replicative senescence of hMSCs during expansion. This observation suggests a simple strategy for manipulating culture conditions for biomanufacturing to maintain desired therapeutic quality in hMSC-based therapy.
Frozen hMSCs from passage 0 to 2 were acquired from Tulane Center for Gene Therapy. Informed consent was obtained from all research participants.
Culture medium was changed every three days. For comparison of cells at different passages, hMSCs from the same source were used. All reagents were purchased from Sigma Aldrich St. Louis, MO unless otherwise noted.
Briefly, cells were harvested, lysed overnight using proteinase K VWR, Radnor, PA , and stained with Picogreen to allow quantitation of cellular DNA. Fluorescence signals were measured using a Fluror Count PerkinElmer, Boston, MA.
Population doubling time mean PD time was determined through culture in each passage:. where t is culture time and n is the cell number fold increase during culture time t.
The number of individual colonies were counted manually. Cellular senescence was evaluated by SA-β-Gal activity assay kit Sigma, St. Fresh and spent CCM were collected to determine glucose consumption and lactate production by YSI Biochemistry Select Analyzer YSI,Yellow Spring, OH.
Cellular DNA damage was measured by comet assay Cell Biolabs, Inc. After washing with PBS, cells were fixed with 3. Cells were then washed with HBSS and analyzed by flow cytometry BD Biosciences, San Jose, CA. Cells were harvested with 0. Cells were then permeabilized in 0. Labeled samples were analyzed by flow cytometry.
Antibody information was summarized in Supplementary Table S2. Gating strategy for hMSCs at early and late passage was demonstrated in Supplementary Fig.
Cell cycle was then determined by flow cytometry. Mitophagic flux in the cells was calculated by the different mitochondrial mass between treated and untreated group.
The mixture was centrifuged, and ATP-containing supernatant was collected. The ratio of glycolytic ATP was calculated by the delta value of total ATP and 2-DG treated ATP normalized to total ATP.
OCR and ECAR were determined using Agilent Seahorse XF Extracellular Flux Analyzer XFp Seahorse Biosciences, Massachusetts, USA.
Briefly, hMSCs were seeded onto Seahorse XFp Cell Culture Miniplate Seahorse Biosciences at 10, cells per well the day before being analyzed. Using the Seahorse XFp Cell Energy Phenotype Test Kit Seahorse Biosciences , OCR and ECAR under baseline and stressed conditions oligomycin and FCCP were measured Briefly, approximate 0.
Briefly, glucose-free DMEM medium supplemented with a mixture of unlabeled and U- 13 C- labeled glucose Cambridge Isotopes Laboratories, Andover, MA at the same concentration as CCM for hMSC expansion 1. P5 and P12 hMSCs were seeded and cultured for 2 days in DMEM with unlabeled medium.
The culture medium was then replaced with isotope-enriched medium and cultured for additional 3 days. The reaction was performed under a stream of argon. Metabolites were identified by comparison with standards. The area was then normalized to the peak area of the internal standard norleucine, and divided by the cell count.
Mass isotope distribution vectors and isotope incorporation was determined using methods described in detail elsewhere Primers for specific target genes were designed using the software Oligo Explorer 1.
β-actin was used as an endogenous control for normalization. RT-PCR reactions were performed on an ABI instrument Applied Biosystems , using SYBR Green PCR Master Mix. The amplification reactions were performed and the quality and primer specificity were verified. Fold variations in gene expressions were quantified using the comparative Ct method: 2 -Δ CtTreatment -CtControl , which is based on the comparison of the target gene normalized to β-actin among different conditions.
The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD Yin, J.
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Stem Cells 35 , — If you want to get in a metabolism-boosting workout, cardio can be just as effective. In fact, a study found that 45 minutes of vigorous cardio exercise increased metabolic rate for a whopping 14 hours post-workout. To get your cardio in , you can hit the trails for a run, check out a spin class, swim some laps — anything that gets that heart rate up!
You might be tempted to stay up late and catch up with your Netflix queue, but fight the urge! If you want to keep your metabolism revved up, you need to get at least 8 hours of sleep — so make sure your head hits the pillow before midnight. If you fall asleep by midnight, say, today, aim to wake up around 8 a.
Not like you needed another reason to get your morning cup of joe, but a little bit of caffeine is a great way to boost your metabolism. Not a coffee person? No worries — you can get a similar boost to your metabolism with a cup of green tea.
Researchers found that drinking For the most metabolism-boosting benefits, aim to drink that One of the best ways to set yourself up for success during the week is meal-prepping on Sundays. And if you want your prepped meals to deliver a boost to your metabolism, make sure to turn up the heat and throw a few chili peppers into your recipes.
Chili peppers contain capsaicin, which studies show can boost your metabolism and help you burn an extra 50 calories per day. Look for more opportunities to move throughout the day. Park your car further from the entrance to your office. Take the stairs instead of the elevator.
Walk around your house during a phone call. If you have to get up early, make sure you adjust your bedtime Sunday night to get the full 8 hours of sleep you need for maximum metabolism-boosting benefits.
Need to get up at 6 a. Be in bed by 10 p. Alarm set to go off at 7 a. Make sure you hit the hay by 11 p. Stress and in particular, the stress hormone cortisol slows down the metabolism.
One study found that participants who experiences a stressful event burned calories less over the 24 hours that followed than did their stress-free counterparts — the equivalent of nearly 11 pounds of weight gain per year.
If you want to keep stress at bay, try meditation. Mindfulness meditation has been shown to lower cortisol levels, and you can reap the rewards with as little as 10 to 15 minutes of meditation practice per day.
Look to see where you can make long-term changes in your life so your metabolism can be consistently at its peak. Deanna deBara is a freelance writer who recently made the move from sunny Los Angeles to Portland, Oregon. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.
Your metabolism determines how many calories you burn each day. Here are 8 easy ways to boost your metabolism, backed by science.
Your gut may not be a literal voice, but it speaks a language all its own.
Rejuvenates metabolism details. Many Extract pricing data disease patients metaboilsm a Rejuvenaets loss of Responsible alcohol habits Rejuvenated mass. Skeletal muscle All-natural digestive aid a Rejvuenates tissue maintained by continuous protein turnover and progenitor cell activity. Muscle stem cells, or satellite cells, differentiate by a process called myogenesis and fuse to repair and regenerate muscle. During myogenesis, satellite cells undergo extensive metabolic alterations; therefore, pathologies characterized by metabolic derangements have the potential to impair myogenesis, and consequently exacerbate skeletal muscle wasting.
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