The Biochemistry of TB-500 (Thymosin Beta-4)

Biochemistry of TB-500

 

TB-500 is a synthetic analog of the active region of thymosin beta-4 (TB4). TB4 is a protein that is active in the sequestration of actin and thus plays a role in actin polymerization. Actin is a globular protein that, when polymerized, forms microfilaments. Microfilaments are fundamental components of cell structure and make up a number of different proteins. These filaments play active roles in cell growth, cell division, cell proliferation, muscle function, and cell longevity.

The Genetics of TB4

TB4 is an interesting protein because the gene that encodes it is found in two variations. The main variation is found on the X chromosome, which is found in both males and females. A variant, known as thymosin beta-4 Y-chromosomal, is found on the male-specific region of the Y chromosome and thus is only found in males. This means that males have an additional thymosin beta gene that is not found in females and which escapes X inactivation1. Though the significance of this additional TB4-like gene has not yet been elucidated, it does appear to play a role in the increased muscle growth seen in male as opposed to female mammals.

TB-500 and Sarcomere Function

The primary components of muscle sarcomeres, the proteins responsible for muscle contraction and thus strength, are actin and myosin. Myosin provides the active component of contraction while active provides the structural component against which myosin acts. Sarcomeres are found primarily in skeletal and cardiac (heart) muscle. Actin is found in smooth muscle, but in a less organized form not associated with sarcomeres.

The most basic role of TB4 is in maintaining a pool of monomeric actin within cells2. This suggests that TB4 is like a storage system for actin. It ensures that actin monomers, the smallest units of actin, are available within cells that will eventually need them to construct larger actin polymers. This, however, is not the only known role of TB4.

During development of myocytes (muscle cells), a particular type of actin known as gamma-actin, plays an important role in the organization and assembly of sarcomeres. In other words, gamma-actin is necessary for sarcomeres to form and develop properly. Gamma-actin is encoded by the ACTG1 gene, a gene that TB4 interacts with. By activating ACTG1, TB4 sets off a chain reaction that helps to ensure proper gamma-actin production and thus proper sarcomere development.

TB4 is also associated with activation of another actin gene known as ACTA1. This gene handles the production of alpha-actin, the primary component of microfilaments in sarcomeres. In sarcomere development, gamma-actin sets up the organization of a sarcomere and then is replaced over time by alpha-actin.

Biochemistry of TB-500

While the exact role of TB4 in actin development is unclear, research in mouse models has found that TB4 administration can reactivate cardiac progenitor cells and aid in the repair of damaged heart tissue3,4. Very recent studies have also suggested that TB4 may inhibit certain cell processes known to interfere with actin arrangement and lead to actin dysfunction5. It appears that TB4 may play roles in both promoting actin arrangement and in preventing other processes from interfering with actin. The end result is increased actin polymerization and thus sarcomere development in both cardiac and skeletal muscle cells. Get more details at http://www.thehorse.com/articles/32150/stiff-penalties-tied-to-drugs-purple-pain-tb-500

Resources

1. Lahn, B. T. & Page, D. C. Functional Coherence of the Human Y Chromosome. Science278, 675-680 (1997).

2. Xue, B., Leyrat, C., Grimes, J. M. & Robinson, R. C. Structural basis of thymosin-β4/profilin exchange leading to actin filament polymerization. Proc. Natl. Acad. Sci. U. S. A.111, E4596-4605 (2014).

3. Smart, N. et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature474, 640-644 (2011).

4. Rui, L. et al. Extending the time window of mammalian heart regeneration by thymosin beta 4. J. Cell. Mol. Med.18, 2417-2424 (2014).

5. Kim, S. & Kwon, J. Actin cytoskeletal rearrangement and dysfunction due to activation of the receptor for advanced glycation end products is inhibited by thymosin beta 4. J. Physiol.593, 1873-1886 (2015).

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