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Oh, Juhyun

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Juhyun

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Oh, Juhyun

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2014 - 20174

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Author's Publications: search.filters.isAuthorOfPublication.c5c9e3f0-ee42-45ed-ad7e-1bac6a872c82

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    Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle
    (American Association for the Advancement of Science (AAAS), 2014) Sinha, Manisha; Jang, Y. C.; Oh, Juhyun; Khong, Danika; Wu, Elizabeth Y; Manohar, Rohan; Miller, Christine; Regalado, Samuel G.; Loffredo, F; Pancoast, James R.; Hirshman, Michael; Lebowitz, Jessica; Shadrach, Jennifer; Cerletti, Massimiliano; Kim, Mi Jeong; Serwold, Thomas; Goodyear, Laurie; Rosner, Bernard; Lee, Richard; Wagers, Amy
    Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral “rejuvenating” factors that can restore regenerative function. Here, we demonstrate that the circulating protein growth differentiation factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction.
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    Cellular and Molecular Mechanisms of Chronic Inflammation in Aging of Skeletal Muscle
    (2015-05-13) Oh, Juhyun; Hsu, Ya-Chieh; Maas, Richard; Fielding, Roger
    Aging of skeletal muscle is typically accompanied by declining regenerative potential, due in part to alternations in the resident muscle stem cell population, known as satellite cells. Previous data suggest that highly regenerative satellite cells in young mice are damaged by aging and chronic inflammation, driven in part by the transcription factor NF-κB. Interestingly, myogenic function of aged satellite cells can be restored by exposure to blood-borne factors from young mice, in association with decreased expression of many of pro-inflammatory genes. These observations led me to hypothesize that strategies counteracting the chronic inflammatory state in muscle might improve regenerative function in old age through enhancement of satellite cell function. To test this hypothesis, this study aims to define the molecular factors that promote chronic muscle inflammation with aging, evaluate their impact on satellite cell functions, and determine whether inhibition of the inflammatory process indeed reverses age-related muscle dysfunction. Utilization of well-established mouse models reveals that NF-κB activity has a detrimental effect on satellite cell function via non-cell-autonomous mechanisms, and that inhibition of NF-κB activity and its downstream target phospholipase A2 in skeletal muscle fibers preserves muscle regenerative potential in aged animals. In addition, this study reports the restrictive role of IL-6, a pro-inflammatory cytokine widely recognized as a biomarker of chronic inflammation, on the myogenic function of satellite cells. Finally, this study shows that systemic inhibition of inflammation using the NF-κB antagonist sodium salicylate decreases inflammatory gene expression, including IL-6, in aged muscle and improves muscle regeneration after injury. Thus, chronic inflammation in muscle, in association with elevated NF-κB activity and its downstream pro-inflammatory factors, impairs muscle regeneration by extrinsically limiting the myogenic function of satellite cells in aged animals. Importantly, such impairment was shown to be reversible by reducing the inflammatory tone both at tissue and systemic level. By discovering the molecular mediators NF-κB signaling in muscle, this study provides potential therapeutic avenues for elderly patients with declining muscle mass and function.
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    Age-associated NF-κB signaling in myofibers alters the satellite cell niche and re-strains muscle stem cell function
    (Impact Journals LLC, 2016) Oh, Juhyun; Sinha, Indranil; Tan, Kah Yong; Rosner, Bernard; Dreyfuss, Jonathan M.; Gjata, Ornela; Tran, Peter; Shoelson, Steven; Wagers, Amy
    Skeletal muscle is a highly regenerative tissue, but muscle repair potential is increasingly compromised with advancing age. In this study, we demonstrate that increased NF-κB activity in aged muscle fibers contributes to diminished myogenic potential of their associated satellite cells. We further examine the impact of genetic modulation of NF-κB signaling in muscle satellite cells or myofibers on recovery after damage. These studies reveal that NF-κB activity in differentiated myofibers is sufficient to drive dysfunction of muscle regenerative cells via cell-non-autonomous mechanisms. Inhibition of NF-κB, or its downstream target Phospholipase A2, in myofibers rescued muscle regenerative potential in aged muscle. Moreover, systemic administration of sodium salicylate, an FDA-approved NF-κB inhibitor, decreased inflammatory gene expression and improved repair in aged muscle. Together, these studies identify a unique NF-κB regulated, non-cell autonomous mechanism by which stem cell function is linked to lipid signaling and homeostasis, and provide important new targets to stimulate muscle repair in aged individuals.
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    Structural basis for potency differences between GDF8 and GDF11
    (BioMed Central, 2017) Walker, Ryan G.; Czepnik, Magdalena; Goebel, Erich J.; McCoy, Jason C.; Vujic, Ana; Cho, Miook; Oh, Juhyun; Aykul, Senem; Walton, Kelly L.; Schang, Gauthier; Bernard, Daniel J.; Hinck, Andrew P.; Harrison, Craig A.; Martinez-Hackert, Erik; Wagers, Amy; Lee, Richard; Thompson, Thomas B.
    Background: Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. Results: Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. Conclusions: These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined. Electronic supplementary material The online version of this article (doi:10.1186/s12915-017-0350-1) contains supplementary material, which is available to authorized users.