02/15/2021
By Matthew Gage
The Kennedy College of Science, Department of Chemistry, invites you to attend a doctoral dissertation defense by Thellambure Pabodha Hettige entitled “Comparative transcriptomic analysis of extensor digitorum longus (EDL), psoas, and soleus muscles from muscular dystrophy with myositis (mdm) mice.”
The defense will be held on Feb. 25 at 12:30 p.m. via Zoom. Please contact Matthew Gage for meeting information if you are interested in attending. The committee will be composed of Matthew Gage (chair), Jin Xu, Kenneth Marx and Frédéric Chain. A brief abstract is provided below.
Abstract: Titin is a giant muscle protein coded by 363 exons in the human genome, and by 347 exons in the mouse genome. There is increasing evidence suggesting titin as a multifunctional protein that engages in passive force generation, active force modulation, mechano-sensing, and gene expression. Understanding the function and associated structural modifications of titin is tackled with a wide array of approaches.
Muscular dystrophy with myositis (mdm) mice is extensive utilized as a model organism to understand titin function. Mdm is caused by a deletion in the titin N2A-PEVK junction, which is part of a mechano-sensing protein complex in skeletal muscles. The disease phenotype contradicts the behavior of common muscular dystrophies, and a majority of the known molecular descriptors in mdm muscles do not align with the observed phenotype.
My dissertation research aimed to decode the molecular level changes leading to the complex mdm disease onset. The comparative analysis of (mdm to wildtype) extensor digitorum longus (EDL), psoas, and soleus muscles collectively indicated a strong directional response in genes encoding mitochondrial structure and function associated proteins. These genes were downregulated in all three muscles and identified hub genes were primarily coding for mitochondrial ribosomal proteins and mitochondrial respiratory chain complex I, III, and V associated proteins. Current data also show changes to the titin splicing pattern in mdm muscles. Expression of Z-repeats was upregulated in fast EDL and psoas, which is generally found in healthy slow muscles. Most splicing changes were concentrated to the N-terminus of PEVK, but the degree of splicing changes observed in EDL, psoas, and soleus was unique to each muscle. The overall changes to titin splicing possibly lead to increased expression of shorter titin isoforms in mdm skeletal muscles. Hence, the increased passive stiffness in mdm muscles could be associated with both increased expression of shorter titin isoforms and the expression changes in extracellular matrix components. The contribution of these two factors to the overall increase in passive stiffness is likely subjective to individual muscles.
All interested students and faculty members are invited to attend.