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Research:

The functional molecular biology laboratory focuses on two areas of musculoskeletal development and adaptation. We are interested in both the transcriptional and translational effects of exercise and in methods for engineering functional musculoskeletal tissues in vitro.

Molecular Biology of Exercise:

Research from our laboratory has identified the mammalian target of rapamycin (mTORC1)/S6 protein kinase (S6K1) pathway as the central mechanism involved in physiological hypertrophy of skeletal muscle in response to resistance exercise (1). It is now clear that resistance exercise activates mTORC1 and that this activation is important in increasing muscle's capacity for protein synthesis. By studying how mTORC1 is activated by resistance exercise and identifying the downstream targets of mTORC1, we hope to find molecules that are critical for muscle growth and can reproduce the increase in muscle mass without the need for the exercise stimulus.

Unlike resistance exercise, endurance exercise results in a coordinated genetic response that increases aerobic capacity. Our laboratory and others have identified a central transcriptional cofactor that is activated following a single bout of aerobic exercise (2, 7). The peroxisome proliferative activated receptor, gamma coactivator (PGC)-1α is a master regulator of mitochondrial biogenesis and enzymes of fatty acid metabolism. It is now clear that many stimuli converge on PGC-1 and that a number of these molecules also inhibit the activation of the mTORC1/S6K1 pathway. Understanding this interplay will be essential if we are to develop genetic or pharmacological interventions to create bigger, stronger, and more fatigue resistant muscles.

Functional Tissue Engineering:
1) Engineering 3D muscle constructs: In parallel to our in vivo exercise studies we have developed and are testing 3 dimensional (3D) engineered skeletal muscle. These tissues can be made from either primary muscle cells (4, 5) or from C2C12 muscle cells (in review). This allows us to test muscle from transgenic mice as well as generate our own inducible overexpression and knockdown cell lines. Engineered muscles from these genetically modified cells can be stimulated electrically or mechanically in a series of bioreactors that we have developed with our collaborators for this purpose. In this way we are testing the effect of different genes on the development of endurance and strength. Click here to see the 3D-Muscle Construct movie.

2) Engineering Musculoskeletal Interfaces: In our bodies, tendons and ligaments connect muscle to bone and bone to bone respectively. Very little is understood as to how these tissues function and even less how these complex interfaces between muscle and bone, and bone and bone can be engineered in vitro. We have developed a series of calcium phosphate based cements that we are using to recreate the tendon/ligament to bone connection. Our engineered tendons are developmentally similar to embryonic tendon/ligament (3, 6). Using these constructs and our calcium phosphate cements, we are attempting to engineer the first in vitro ligament (bone-ligament-bone) with the hope of implanting these tissues into animals and in the future udreamworkssing them to repair ligaments in humans after rupture. Click here to see a movie showing a ligament being tested.

Further Readings:
1. Baar K, and Esser K. Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise. Am J Physiol 276: C120-127, 1999.
2. Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP, and Holloszy JO. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. Faseb J 16: 1879-1886, 2002.
3. 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 Jul 1. [Epub ahead of print]
4. Huang YC, Dennis RG, and Baar K. Cultured slow vs. fast skeletal muscle cells differ in physiology and responsiveness to stimulation. Am J Physiol Cell Physiol 2006.
5. Huang YC, Dennis RG, Larkin L, and Baar K. Rapid formation of functional muscle in vitro using fibrin gels. J Appl Physiol 98: 706-713, 2005.
6. Kapacee Z, Richardson SH, Lu Y, Starborg T, Holmes DF, Baar K, and Kadler KE. Tension is required for fibripositor formation. Matrix Biol 27: 371-375, 2008.
7. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, and Spiegelman BM. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98: 115-124, 1999.

 


Last updated: July 30, 2010
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