ROLE OF TITIN IN FUNCTIONAL TRANSITIONS DURING MUSCLE DEVELOPMENT AND AGING

Research project

Description

DESCRIPTION (provided by applicant): Titin is a giant elastic protein that constitutes the third myofilament of the sarcomere and that performs a wide range of functions. Our long-term objective is to understand the role titin in cell signaling, protein turnover, and mechanics. Our recent work and that of others has revealed that differential splicing of titin has a pronounced effect on myofibrillar passive stiffness and we showed that the lowest stiffness results from expressing fetal cardiac titin isoforms. Less well understood is the importance of titin, relative to that of collagen, for tissue and organ level stiffness. Here we propose to study the contribution of both titin and collagen to the changes in stiffness that occur during postnatal development of cardiac and skeletal muscle, by performing experiments from the molecular to the isolated heart levels. A second goal is to study the role of titin and collagen in the changes in passive stiffness of both the heart and skeletal muscle that occur during aging. These experiments include study of alternative splicing (using a novel titin exon microarray) and posttranslational modifications of titin, as mechanisms for modulating titin- based passive stiffness during aging. Preliminary findings highlight the importance of this work. Finally, titin also interacts with many small proteins, some of which are involved in regulating protein turnover. Our last aim will focus on the ubiquitin ligase MURF-1 that binds adjacent to titin's kinase domain. MURF-1 is highly upregulated in various models of skeletal muscle atrophy and was recently shown to impair contractility of cardiac myocytes. These and related findings have led to the notion that MURF-1 controls processes that determine the balance between hypertrophic and atrophic signals. We propose to investigate the roles of MURF-1 in cardiac hypertrophy (aortic banding model) as well as in the skeletal muscle atrophy that occurs in senescent muscle, by using a MURF-1 KO model that we developed. The proposed research will increase understanding of titin as an elastic element in striated muscle and will contribute to a mechanistic understanding of changes in diastolic filling of the heart during development and aging. This is significant because diastolic dysfunction is a high risk factor for perinatal mortality, and age is a key factor that increases the risk of diastolic heart failure and skeletal muscle dysfunction. Our studies of MURF-1 are expected to contribute to understanding of molecular mechanisms that underlie striated muscle hypertrophy and atrophy, in health and disease.
StatusFinished
Effective start/end date7/1/074/30/13

Funding

  • National Institutes of Health: $377,500.00
  • National Institutes of Health: $377,500.00
  • National Institutes of Health: $377,500.00
  • National Institutes of Health: $377,500.00
  • National Institutes of Health: $377,500.00

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Connectin
Muscle Development
Skeletal Muscle
Proteins
Muscular Atrophy
Myocardium
Collagen
Striated Muscle
Diastolic Heart Failure
Sarcomeres
Myofibrils
Perinatal Mortality
Alternative Splicing
Cardiomegaly
Post Translational Protein Processing
Ligases
Ubiquitin
Mechanics
Cardiac Myocytes
Hypertrophy

Keywords

  • Medicine(all)