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PESC Pilot Project - Year 4

Liz Lyons, PhDAndres Oberhauser, PhD
Professor, Neuroscience & Cell Biology
Mentor: Blake Rasmussen, PhD

Titin Nano-Mechanics in Age-Related Sarcopenia

One of the most remarkable effects of age is the loss of muscle mass, strength, and function, termed sarcopenia. The loss of muscle mass and strength with aging is a highly prevalent condition among older adults and predicts several adverse outcomes, including a decrease in functional performance, increased mobility-related disabilities and greater risk of falls in the elderly.

The molecular mechanisms underlying sarcopenia are still not well understood. Animals have complex mechanisms to regulate their overall muscle mass. An attractive emerging concept is that the giant elastic protein titin plays a key role in modulating myofibril growth. Titin interacts with a large number of muscle proteins, has been shown to function as a mechanosensor.

Our central hypothesis is that during the aging process titin undergoes oxidative modifications that correlate with changes in its elastic and mechanosensing properties. These changes may ultimately contribute to the diminished muscle mass in sarcopenia. To test our hypothesis we will use a combination of single-molecule and biochemical techniques. In Aim 1, we will measure and compare the nano-mechanical properties of native skeletal titin from young (3-6 months) and aged (18-24 months) mice. We will measure several key nano-mechanical parameters such as domain unfolding kinetics, relaxation speed, entropic elasticity and overall flexibility. To map potential irreversible post-translational oxidative modifications we will purify titin proteolytic fragments from the elastic part of titin and perform mass spectrometric analysis. In Aim 2, we will use recombinantly expressed titin fragments in the presence of mixtures of oxidant and reducing agents and evaluate their effects on the nano-mechanical properties of the elastic domains and titin mechano-enzymatic activity.

This research is significant because titin is essential for the development, structure and function of skeletal muscles. Our experiments will provide complementary information on the molecular mechanisms underlying decreased muscle mass in the elderly. Our studies may lead to the development new therapeutic strategies, using rational drug design, to target different titin domains (e.g. the kinase domain) in order to improve muscle performance in the elderly.

 

 

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