Keith Baar, Ph.D.
Professor in Residence
195 Briggs Hall
The goal of my laboratory is to understand the molecular determinants of musculoskeletal development and the role of exercise in improving health and performance. To achieve this goal, we work on muscle, tendon, and ligaments from 2- and 3-dimensional tissue culture, in vivo wild type and genetically modified animals, and humans. Of particular interest are: 1) the interplay between nutrition and exercise and the mammalian target of rapamycin complex 1 (mTORC1) in the maintenance of muscle mass; 2) the role of the amino acid transceptor LAT1 in the activation of protein synthesis and maintenance of muscle mass; 3) the mechanism of ER stress-induced loss of protein synthesis and how this leads to anabolic resistance in muscle; and 4) the role of growth factors and loading on the activation of the Egr-1 transcription factor and the development and mechanics of ligaments. Our laboratory discovered that mTORC1 was activated by resistance exercise and that this correlates with the degree of skeletal muscle hypertrophy. Since then, we have focused on mTORC1 and its regulation by loading and nutrients. We have shown that: 1) mTORC1 is activated directly by load in a growth factor-independent manner; 2) a1-AMPK regulates mTORC1 activity during overload; 3) following a high fat diet the unfolded protein response, through inhibition of PKB, can attenuate mTORC1 activation; and 4) muscle signaling and protein synthesis after exercise are modified by nutritional interventions that are rich in leucine. Our laboratory has also developed a number of 2- and 3-dimensional tissue culture assays that can be used to study the effects of genes and nutrients on muscle, tendon, and ligament function. These studies have a direct clinical application and we work closely with colleagues in orthopedics, internal medicine, and the cancer center to develop resistance exercise, nutritional, and novel small molecule interventions that prevent muscle wasting from cachexia and sarcopenia and improve muscle function and quality of life.
For more information, please visit: The Functional Molecular Biology Lab
McGee SL, Swinton C, Morrison S, Gaur V, Campbell DE, Jorgensen SB, Kemp BE, Baar K, Steinberg GR, Hargreaves M. Compensatory regulation of HDAC5 in muscle maintains metabolic adaptive responses and metabolism in response to energetic stress. FASEB J. 2014 Apr 14. [Epub ahead of print]
Wecksler, A.T., S.H. Hwang, H.I. Wettersten, J.E. Gilda, A. Patton, L.J. Leon, K.L. Carraway 3rd, A.V. Gomes, K. Baar, R.H. Weiss, B.D. Hammock. Novel sorafenib-based structural analogues: in-vitro anticancer evaluation of t-MTUCB and t-AUCMB. Anticancer Drugs. 2014 Apr;25(4):433-46.
Philp, A., M.G. MacKenzie, M.Y. Belew, M.C. Towler, A. Corstorphine, A. Papalamprou, D. G. Hardie, and K. Baar. Glycogen Content Regulates Peroxisome Proliferator Activated Receptor-∂ (PPAR-∂) Activity in Rat Skeletal Muscle. PLOS ONE 2013 Oct 17;8(10):e77200.
Hwee D.T., L.M. Baehr, A. Philp, K. Baar, and S.C. Bodine. Maintenance of muscle mass and load-induced growth in Muscle RING Finger 1 null mice with age. Aging Cell. 2013. EPub.
Mackenzie, M.G., D.L. Hamilton, M. Pepin, A. Patton, and K. Baar. Inhibition of Myostatin Signaling through Notch Activation following Acute Resistance Exercise. PLoS One. 2013 Jul 2;8(7):e68743.
Timmons, J.A., K. Baar, P. Davidsen, and P.J. Atherton. Is irisin a human exercise gene? Nature. 2012 488(7413): E9-10
Hagerty, P., A. Lee, S. Calve, C.A. Lee, M. Vidal, and K. Baar. The effect of growth factors on both collagen synthesis and tensile strength of engineered human ligaments. Biomaterials. 2012 Sep;33(27):6355-61.
Churchward-Venne, T.A., N.A. Burd, C.J. Mitchell, D.W. West, A. Philp, G.R. Marcotte, S.K. Baker, K. Baar, and S.M. Phillips. Supplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in men. J Physiol. 2012 Jun 1;590(Pt 11):2751-65.
Park, S.J., F. Ahmad, A. Philp, K. Baar, T. Williams, H. Luo, H. Ke, H. Rehmann, R. Taussig, A.L. Brown, M.K. Kim, M.A. Beaven, A.B. Burgin, V. Manganiello, J.H. Chung. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell. 2012 Feb 3;148(3):421-33.
Khodabukus, A., and K. Baar. Defined electrical stimulation emphasizing excitability for the development and testing of engineered skeletal muscle. Tissue Eng Part C Methods. 2012 May;18(5):349-57.
Paxton J.Z., P. Hagerty, J.J. Andrick, and K. Baar. Optimizing an intermittent stretch paradigm using ERK1/2 phosphorylation results in increased collagen synthesis in engineered ligaments. Tissue Eng Part A. 2012 Feb;18(3-4):277-84.
Schenk S., C.E. McCurdy, A. Philp, M.Z. Chen, M.J. Holliday, G.K. Bandyopadhyay, O. Osborn, K. Baar, and J.M. Olefsky. Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. J Clin Invest. 2011 Nov 1;121(11):4281-8.
Philp, A., M.Y. Belew, A. Evans, D. Pham, I. Sivia, A. Chen, S. Schenk, and K. Baar. The PGC-1a related co-activator (PRC) promotes mitochondrial and myogenic adaptations in C2C12 myotubes. Am J Physiol Regul Integr Comp Physiol. 2011 Oct;301(4):R864-72.
Philp, A., A. Chen, D. Lan, G.A. Meyer, A.N. Murphy, A.E. Knapp, I.M. Olfert, C.E. McCurdy, G.R. Marcotte, M.C. Hogan, K. Baar, and S. Schenk. Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator activated receptor g coactivator-1a (PGC-1a) deacetylation following endurance exercise. J Biol Chem. 2011 Sep 2;286(35):30561-70.
Breen, L., A. Philp, O.C. Witard, S.R. Jackman, A. Selby, K. Smith, K. Baar, and K.D. Tipton. The influence of carbohydrate-protein co-ingestion following endurance exercise on myofibrillar and mitochondrial protein synthesis. J Physiol. 2011 Aug 15;589(Pt 16):4011-25.
Deldicque L., L. Bertrand, A. Patton, M. Francaux, and K. Baar. ER Stress Induces Anabolic Resistance in Muscle Cells through PKB-Induced Blockade of mTORC1. PLoS ONE 2011 6(6): e20993.
Preston, R.S., A. Philp, T. Claesens, E.A. Dunlop, L. Gijezen, K.T. Harper, T. Brinkhuizen, D.M. Davies, S.S. Land, K. Baar, M. van Steensel and A.R. Tee. Absence of the Birt-Hogg-Dubé gene product is associated with increased Hypoxia Inducible Factor transcriptional activity and a loss of metabolic flexibility. Oncogene, 2011 Mar 10;30(10):1159-73.
Hamilton D.L., A. Philp, M.G. MacKenzie, and K. Baar. A limited role for PI(3,4,5)P3 regulation in controlling skeletal muscle mass in response to resistance exercise. PLoS One. 2010 Jul 16;5(7):e11624.
Paxton J.Z., L.M. Grover, and K. Baar. Engineering an In Vitro Model of a Functional Ligament from Bone to Bone. Tissue Eng Part A. 2010 Nov;16(11):3515-25.
Deldicque L, P.D. Cani, A. Philp, J.M. Raymackers, P.J. Meakin, M.L. Ashford, N.M. Delzenne, M. Francaux, and K. Baar. The unfolded protein response is activated in skeletal muscle by high-fat feeding: potential role in the down-regulation of protein synthesis. Am J Physiol Endocrinol Metab. 2010 Nov;299(5):E695-705.
Bayer M.L., C.Y. Yeung, K.E. Kadler, K. Qvortrup, K. Baar, R.B. Svensson, S.P. Magnusson, M. Krogsgaard, M. Koch M, and M. Kjaer. The initiation of embryonic-like collagen fibrillogenesis by adult human tendon fibroblasts when cultured under tension. Biomaterials. 2010 Jun;31(18):4889-97.
Hulston, C.J., M.C. Venables, C.H. Mann, C. Martin, A. Philp, K. Baar, and A.E. Jeukendrup. Training with low muscle glycogen enhances adaptations in fat metabolism in well-trained cyclists. Med Sci Sports Exerc. 2010 Nov;42(11):2046-55.
Khodabukus, A., and K. Baar. Regulating Fibrinolysis to Engineer Skeletal Muscle from the C2C12 Cell Line. Tissue Eng Part C Methods. 2009 Sep;15(3):501-11.
MacKenzie, M.G., D.L. Hamilton, J.T. Murray, P.M. Taylor, and K. Baar. mVps34 is activated following high-resistance contractions. J Physiol. 2009 Jan 15;587(Pt 1):253-60.
Paxton, J.Z., K. Donnelly, R.P. Keatch, and K. Baar. Engineering the Bone-Ligament Interface Using Polyethylene Glycol Diacrylate Incorporated with Hydroxyapatite. Tissue Eng Part A. 2009 Jun;15(6):1201-9.
Kapacee, Z., S.H. Richardson, Y. Lu, T. Starborg, D.F. Holmes, K. Baar, and K.E. Kadler. Tension is required for fibripositor formation. Matrix Biology, 2008 27:371–375.
McGee, S.L., K.J. Mustard, D.G. Hardie, and K. Baar. Normal Hypertrophy Accompanied by Phosphoryation and Activation of AMPK-α1 Following Overload in LKB1 Knockout Mice. J Physiol. 2008 Mar 15;586(6):1731-41.
Cuthbertson D.J., J. Babraj, G.P. Leese, K. Baar, K.J.W. Mustard, K. Smith, C. Sutherland, D.G. Hardie, and M.J. Rennie. AICAR acutely stimulates skeletal muscle glucose uptake in healthy men. Diabetes. 2007 Aug;56(8):2078-84.
Timmons J.A., K. Wennmalm, O. Larsson, T.B. Walden, T. Lassmann, N. Petrovic, D.L. Hamilton, R.E. Gimeno, C. Wahlestedt, K. Baar, J. Nedergaard, and B. Cannon. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4401-6.
Arruda E.M., K. Mundy, S. Calve,,and K. Baar. Denervation does not change the ratio of collagen I and collagen III mRNA in the extracellular matrix of muscle. Am J Physiol Endocrinol Metab. 2007 Feb;292(2):R983-7.
Arruda EM, Calve S, Dennis RG, Mundy K, Baar K. Regional variation of tibialis anterior tendon mechanics is lost following denervation. J Appl Physiol. 2006 Oct;101(4):1113-7.
Huang YC, Dennis RG, Baar K. Cultured slow vs. fast skeletal muscle cells differ in physiology and responsiveness to stimulation. Am J Physiol Cell Physiol. 2006 Jul;291(1):C11-7.
Hecker, L., K. Baar, and K.N. Bitar. Development of a 3-Dimensional Physiological Model of the Internal Anal Sphincter Bioengineered in-vitro from Isolated Smooth Muscle Cells. Amer. J. Physiol.: Gastrointest Liver Physiol, 2005 Aug;289: G188-G196.
Baar, K., R. Birla, M.O. Boluyt, G.H. Borschel, E.M. Arruda, and R.G. Dennis. Heart muscle by design: self-organization of rat cardiac cells into contractile 3-D cardiac tissue. FASEB J. 2005 Feb;19(2):275-7.
Huang, Y-C, R.G. Dennis, and K. Baar. Rapid formation of functional muscle in vitro using fibrin gels. Feb 2005; 98: 706 - 713.
Calve, S.C., R.G. Dennis, P.E. Kosnik II, K. Baar, K. Grosh and E.M. Arruda. Engineering of functional tendon. Tissue Engineering 2004 10(5/6): p. 755-761.
Baar, K., Z. Song, C.F. Semenkovich, T.E. Jones, D.H. Han, L.A. Nolte, E.O. Ojuka, M. Chen, and J.O. Holloszy. Overexpression of nuclear respiratory factor 1 increases muscle glucose transport capacity. FASEB J. 2003 17(12): p. 1666-1673.
Baar, K., A.R. Wende, T.E. Jones, M. Marison, L.A. Nolte, M. Chen, D.P. Kelly, and J.O. Holloszy. Adaptation of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J. 2002 16: 1879-1886.
Chen, Y.W., G. Nader, K. Baar, M. Fedele, E.P. Hoffman, and K.A. Esser. Response of muscle to acute resistance exercise defined by transcriptional and translational profiling. J. of Physiol. 2002 Nov 15;545(Pt 1):27-41.
Baar, K., C. E. Torgan, W. E. Kraus, and K. A. Esser. Autocrine phosphorylation of the 70 KDa S6 protein kinase in response to acute stretch in C2C12 myotubes. Mol. Cell Biol. Res. Comm. 2001: 76-80.
Baar, K., and K. A. Esser. Activation of p70S6k correlates with skeletal muscle hypertrophy in the rat. Amer. J. Physiol. 1999, 276 (Cell Physiol. 45): C120-C127.