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Ronald L. Neppl, Ph.D.

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Overview
Our laboratory is focused on the molecular regulation of skeletal muscle homeostasis in health and disease. Our overarching goal is to understand how ncRNAs control the essential processes of myogenesis and hypertrophic growth, and how perturbations in these processes may lead to a disease state resulting in muscle atrophy. Using traditional biochemical and molecular biology techniques, in vivo and in vitro model systems, as well as next generation RNA sequencing, we seek to discover and understand the biological roles these ncRNAs play in the maintenance of lean muscle mass. Research activities in the laboratory fall within two main project areas:

1) lncRNA mediated regulation of skeletal muscle homeostasis and repair

Mechanistically, multiple cellular and molecular pathways regulating hypertrophic growth (anabolic pathways) and atrophy (catabolic pathways) are known. The major players regulating protein synthesis (i.e. Akt1, Igf1, mTor, SMADs 1/5/8, etc.) and protein degradation (i.e. Atrogin-1, MuRF1, MUSA, FOXO factors, etc.) have been well studied in the context of muscle hypertrophy and atrophy. Though much has been learned regarding the roles of these and other genes, we know relatively little about the roles of lncRNAs in physiological homeostasis of muscle and the progression of disease resulting in atrophy. Though still an emerging field, lncRNAs have been identified as critical regulators of essential cellular processes including cellular differentiation, fate determination, proliferation, and senescence. However, our knowledge of lncRNAs in skeletal muscle physiology is still in its infancy. The primary goal of this project is to understand the functions of lncRNAs in the maintenance of cellular and physiological homeostasis and in the etiology of muscle atrophy.

2) Regulation of the RNA Induced Silencing Complex is necessary for muscle homeostasis and physiological adaptations to stress

The RNA Induced Silencing Complex (RISC) is an evolutionarily conserved, multi-protein regulatory complex responsible for post-transcriptional gene regulation. Functionally, RISC inhibits translation of mRNA into protein through miRNA directed complementary binding to the 3’ untranslated region (UTR) of mRNA resulting loss of mRNA stability via removal of the 5’ m7G cap, deadenylation of the poly(A) tail, or through miRNA directed endonuclease activity. Given the biological necessity of miRNA/RISC, it is unclear how cells positively and negatively regulate its repressive (either endonuclease cleavage and/or mRNA destabilization) effects on mRNA translation to maintain physiological homeostasis. While much is known about the role of individual miRNAs in the regulation of muscle homeostasis and repair, the muscle specific signals and players regulating the activity of this essential muli-protein complex are relatively unknown. It is the overall goal of this project to understand signaling events that regulate the activity of miRNA/RISC under normal and pathological conditions.

Bibliographic
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
  1. Guadagnin E, Bagchi D, Sinha I, Neppl RL. Nuclear localized Akt limits skeletal muscle derived fibrotic signaling. Biochem Biophys Res Commun. 2019 Jan 15; 508(3):838-843. PMID: 30528731.
    Citations:    Fields:    
  2. Panayi AC, Orkaby AR, Sakthivel D, Endo Y, Varon D, Roh D, Orgill DP, Neppl RL, Javedan H, Bhasin S, Sinha I. Impact of frailty on outcomes in surgical patients: A systematic review and meta-analysis. Am J Surg. 2018 Nov 27. PMID: 30509455.
    Citations:    Fields:    
  3. Neppl RL, Wu CL, Walsh K. lncRNA Chronos is an aging-induced inhibitor of muscle hypertrophy. J Cell Biol. 2017 11 06; 216(11):3497-3507. PMID: 28855249.
    Citations:    Fields:    Translation:AnimalsCells
  4. Neppl RL, Kataoka M, Wang DZ. Crystallin-aB regulates skeletal muscle homeostasis via modulation of argonaute2 activity. J Biol Chem. 2014 Jun 13; 289(24):17240-8. PMID: 24782307.
    Citations: 9     Fields:    Translation:HumansAnimalsCells
  5. Neppl RL, Wang DZ. The myriad essential roles of microRNAs in cardiovascular homeostasis and disease. Genes Dis. 2014 Mar 01; 1(1):18-39. PMID: 25328909.
    Citations: 6     
  6. Tao Y, Neppl RL, Huang ZP, Chen J, Tang RH, Cao R, Zhang Y, Jin SW, Wang DZ. The histone methyltransferase Set7/9 promotes myoblast differentiation and myofibril assembly. J Cell Biol. 2011 Aug 22; 194(4):551-65. PMID: 21859860.
    Citations: 32     Fields:    Translation:HumansAnimalsCells
  7. Neppl RL, Wang DZ. 'CArG'ing for microRNAs. Gastroenterology. 2011 Jul; 141(1):24-7. PMID: 21620846.
    Citations:    Fields:    Translation:HumansAnimalsCells
  8. Zieba BJ, Artamonov MV, Jin L, Momotani K, Ho R, Franke AS, Neppl RL, Stevenson AS, Khromov AS, Chrzanowska-Wodnicka M, Somlyo AV. The cAMP-responsive Rap1 guanine nucleotide exchange factor, Epac, induces smooth muscle relaxation by down-regulation of RhoA activity. J Biol Chem. 2011 May 13; 286(19):16681-92. PMID: 21454546.
    Citations: 29     Fields:    Translation:HumansAnimalsCells
  9. Hoofnagle MH, Neppl RL, Berzin EL, Teg Pipes GC, Olson EN, Wamhoff BW, Somlyo AV, Owens GK. Myocardin is differentially required for the development of smooth muscle cells and cardiomyocytes. Am J Physiol Heart Circ Physiol. 2011 May; 300(5):H1707-21. PMID: 21357509.
    Citations: 19     Fields:    Translation:AnimalsCells
  10. Nguyen AT, Xiao B, Neppl RL, Kallin EM, Li J, Chen T, Wang DZ, Xiao X, Zhang Y. DOT1L regulates dystrophin expression and is critical for cardiac function. Genes Dev. 2011 Feb 01; 25(3):263-74. PMID: 21289070.
    Citations: 40     Fields:    Translation:HumansAnimalsCells
  11. Huang ZP, Neppl RL, Wang DZ. Application of microRNA in cardiac and skeletal muscle disease gene therapy. Methods Mol Biol. 2011; 709:197-210. PMID: 21194029.
    Citations: 7     Fields:    Translation:HumansCells
  12. Huang ZP, Neppl RL, Wang DZ. MicroRNAs in cardiac remodeling and disease. J Cardiovasc Transl Res. 2010 Jun; 3(3):212-8. PMID: 20560042.
    Citations: 14     Fields:    Translation:HumansAnimals
  13. Neppl RL, Wang DZ. Smooth(ing) muscle differentiation by microRNAs. Cell Stem Cell. 2009 Aug 07; 5(2):130-2. PMID: 19664984.
    Citations: 4     Fields:    Translation:HumansAnimalsCells
  14. Neppl RL, Lubomirov LT, Momotani K, Pfitzer G, Eto M, Somlyo AV. Thromboxane A2-induced bi-directional regulation of cerebral arterial tone. J Biol Chem. 2009 Mar 06; 284(10):6348-60. PMID: 19095646.
    Citations: 24     Fields:    Translation:AnimalsCells
  15. Wooldridge AA, Fortner CN, Lontay B, Akimoto T, Neppl RL, Facemire C, Datto MB, Kwon A, McCook E, Li P, Wang S, Thresher RJ, Miller SE, Perriard JC, Gavin TP, Hickner RC, Coffman TM, Somlyo AV, Yan Z, Haystead TA. Deletion of the protein kinase A/protein kinase G target SMTNL1 promotes an exercise-adapted phenotype in vascular smooth muscle. J Biol Chem. 2008 Apr 25; 283(17):11850-9. PMID: 18310078.
    Citations: 13     Fields:    Translation:HumansAnimalsCells
  16. Sinha S, Wamhoff BR, Hoofnagle MH, Thomas J, Neppl RL, Deering T, Helmke BP, Bowles DK, Somlyo AV, Owens GK. Assessment of contractility of purified smooth muscle cells derived from embryonic stem cells. Stem Cells. 2006 Jul; 24(7):1678-88. PMID: 16601077.
    Citations: 27     Fields:    Translation:AnimalsCells
  17. Neppl R, Nguyen CM, Bowen W, Al-Saadi T, Pallagi J, Morris G, Mueller W, Johnson R, Prost R, Rand SD. In vivo detection of postictal perturbations of cerebral metabolism by use of proton MR spectroscopy: preliminary results in a canine model of prolonged generalized seizures. AJNR Am J Neuroradiol. 2001 Nov-Dec; 22(10):1933-43. PMID: 11733328.
    Citations: 6     Fields:    Translation:AnimalsCTClinical Trials
  18. Butzen J, Prost R, Chetty V, Donahue K, Neppl R, Bowen W, Li SJ, Haughton V, Mark L, Kim T, Mueller W, Meyer G, Krouwer H, Rand S. Discrimination between neoplastic and nonneoplastic brain lesions by use of proton MR spectroscopy: the limits of accuracy with a logistic regression model. AJNR Am J Neuroradiol. 2000 Aug; 21(7):1213-9. PMID: 10954271.
    Citations: 3     Fields:    Translation:Humans
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Funded by the NIH/NCATS Clinical and Translational Science Award (CTSA) program, grant number UL1TR001102, and through institutional support from Harvard University, Harvard Medical School, Harvard T.H. Chan School of Public Health, Beth Israel Deaconess Medical Center, Boston Children's Hospital, Brigham and Women's Hospital, Massachusetts General Hospital and the Dana Farber Cancer Institute.