Can exosomes be used to treat Sarcopenia?
Image credit: Ryan McGuire from Pixabay
Cruz-Jentoft AJ, Landi F, Schneider SM, Zuniga C, Arai H, Boirie Y, Chen LK, Fielding RA, Martin FC, Michel JP, Sieber C, Stout JR, Studenski SA, Vellas B, Woo J, Zamboni M, Cederholm T: Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing 2014;43:748-759.
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Feedback on the Proposed Usage of Exosomes
Using CRISPR to target Myostatin Gene
- CRISPR is already being tested in muscle cells
- There are already in place plenty of protocols to deliver CRISPR in vivo to skeletal muscle cells
- has been involved in the activation of the SMAD/SMAD3 signalling which is involved in priming muscle atrophy
- Also, MSTN deficient young patients are characterized by muscle hypertrophy .
- check for possible off-targets as well as DSB induced gross rearrangements
- if off-targets are found, we may have to devise strategies to reduce off-targets. Some of those have been described in this session
- use DSB-free alternatives like base-editing or prime editing. These have been described also in the session linked above. However, at the moment the size of base-editors and prime-editors are prohibitive to be packaged in a single viral vector. To this regard, technological advancements will be required for the delivery of these tools in vivo as well.
Enhanced CRISPR-Cas9 correction of Duchenne muscular dystrophy in mice by a self-complementary AAV delivery system BY YU ZHANG, HUI LI, YI-LI MIN, EFRAIN SANCHEZ-ORTIZ, JIAN HUANG, ALEX A. MIREAULT, JOHN M. SHELTON, JIWOONG KIM, PRADEEP P. A. MAMMEN, RHONDA BASSEL-DUBY, ERIC N. OLSON SCIENCE ADVANCES19 FEB 2020 : EAAY6812
Cohen, S, Nathan, JA and Goldberg, AL (2015). Muscle wasting in disease: molecular mechanisms and promis- ing therapies. Nat Rev Drug Discov 14: 58–74.
Lee, YS, Huynh, TV and Lee, SJ (2016). Paracrine and endocrine modes of myostatin actin. J Appl Physiol (1985) 120: 592–598.
Prevention of Muscle Wasting by CRISPR/Cas9-mediated Disruption of Myostatin In Vivo Wei, Yuda et al. Molecular Therapy, Volume 24, Issue 11, 1889 - 1891
Weng, S., Gao, F., Wang, J. et al. Improvement of muscular atrophy by AAV–SaCas9-mediated myostatin gene editing in aged mice. Cancer Gene Ther (2020). https://doi.org/10.1038/s41417-020-0178-7
Systemic gene transfer reveals distinctive muscle transduction profile of tyrosine mutant AAV-1, -6, and -9 in neonatal dogs Hakim, Chady H et al. Molecular Therapy - Methods & Clinical Development, Volume 1, 14002
Langley B, Thomas M, Bishop A, Sharma M, Gilmour S, Kambadur R. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J Biol Chem. 2002 Dec 20;277(51):49831-40. doi: 10.1074/jbc.M204291200. Epub 2002 Sep 18. PMID: 12244043.
Using Biological Scaffolds
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Dziki J, Badylak S, Yabroudi M, Sicari B, Ambrosio A, Stearns K, Turner N, Wyse A, Boninger M, Brown E, Rubin J: An acellular biologic scaffold treatment for volumetric muscle loss: results of a 13-patient cohort Study. Nature Regenerative Medicine 2016
Brown BN, Ratner BD, Goodman SB, Amar S, Badylak SF: Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials 2012;33:3792-3802.
Freytes DO, Martin J, Velankar SS, Lee AS, Badylak SF: Preparation and rheological characterization of a gel form of the porcine urinary bladder matrix. Biomaterials 2008;29:1630-1637.
Natural compounds to treat sarcopenia
- In Chang's study, the researchers found that oligonol a compound commonly found in lychees could improve the grip strength and muscle mass of senescence‐accelerated mouse prone 8 mice.
- Tomatidine is from green tomatoes (unripe tomatoes). Tomatidine supplementation was able to improve muscle mass and grip strength in aged mice.
- Ryu and colleagues found that urolithin A was able to activate mitophagy in elderly mice. This led to an increase in muscle function. Urolithin is in berries, nuts, and pomegranates.
Chang, Yun‐Ching, et al. "Oligonol alleviates sarcopenia by regulation of signaling pathways involved in protein turnover and mitochondrial quality." Molecular nutrition & food research 63.10 (2019): 1801102.
Ebert, Scott M., et al. "Identification and small molecule inhibition of an activating transcription factor 4 (ATF4)-dependent pathway to age-related skeletal muscle weakness and atrophy." Journal of Biological Chemistry 290.42 (2015): 25497-25511.
Ryu, Dongryeol, et al. "Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents." Nature medicine 22.8 (2016): 879-888.
Targeting the Senescent Associated Secretory Phenotype (SASP)
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Yin H, Price F, Rudnicki MA. Satellite cells and the muscle stem cell niche. Physiol Rev. 2013;93(1):23-67. doi:10.1152/physrev.00043.2011
Sugihara H, Teramoto N, Yamanouchi K, Matsuwaki T, Nishihara M. Oxidative stress-mediated senescence in mesenchymal progenitor cells causes the loss of their fibro/adipogenic potential and abrogates myoblast fusion. Aging (Albany NY). 2018;10(4):747-763. doi:10.18632/aging.101425
Casella G, Munk R, Kim KM, Piao Y, De S, Abdelmohsen K, Gorospe M. Transcriptome signature of cellular senescence. Nucleic Acids Res. 2019 Aug 22;47(14):7294-7305. doi: 10.1093/nar/gkz555. Erratum in: Nucleic Acids Res. 2019 Dec 2;47(21):11476. PMID: 31251810; PMCID: PMC6698740.
Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118. doi:10.1146/annurev-pathol-121808-102144
Marjolein P Baar, Eusebio Perdiguero, Pura Muñoz-Cánoves, Peter LJ de Keizer, Musculoskeletal senescence: a moving target ready to be eliminated, Current Opinion in Pharmacology, Volume 40, 2018, Pages 147-155, ISSN 1471-4892, https://doi.org/10.1016/j.coph.2018.05.007.
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O’Leary, M.F., Wallace, G.R., Bennett, A.J. et al. IL-15 promotes human myogenesis and mitigates the detrimental effects of TNFα on myotube development. Sci Rep 7, 12997 (2017). https://doi.org/10.1038/s41598-017-13479-w
Kale A, Sharma A, Stolzing A, Desprez PY, Campisi J. Role of immune cells in the removal of deleterious senescent cells. Immun Ageing. 2020;17:16. Published 2020 Jun 3. doi:10.1186/s12979-020-00187-9
Inhibition of Natural Killer Cell Cytotoxicity by Interleukin‐6: Implications for the Pathogenesis of Macrophage Activation Syndrome Loredana Cifaldi Giusi Prencipe Ivan Caiello Claudia Bracaglia Franco Locatelli Fabrizio De Benedetti Raffaele Strippoli
Guozhu Xie, Han Dong, Yong Liang, James Dongjoo Ham, Romee Rizwan, Jianzhu Chen, CAR-NK cells: A promising cellular immunotherapy for cancer, EBioMedicine, Volume 59, 2020, 102975, ISSN 2352-3964, https://doi.org/10.1016/j.ebiom.2020.102975.