This project's goal is to elucidate the mechanisms responsible for the decline in skeletal muscle performance with aging. We propose that JP-45 regulates SR Ca2+ release elicited by DHPR-RyR1 coupling and that the JP-45/DHPR11 complex is crucial to the age-dependent decrease in muscle specific force. Hypotheses:
The specific aims will test the hypotheses that JP-45 plays a role in DHPR11 subunit expression and that it's age-dependent down regulation leads to decreased DHPR11 expression, contributing to the decline in SR Ca2+ release and specific force in skeletal muscle fibers from senescent mice.
Aim 1. To establish that JP-45 KO leads to decreased DHPR11 subunit expression by increasing its rate of degradation in skeletal muscle from adult mice. We have previously demonstrated that JP-45 KO leads to decreased DHPR11 subunit expression, charge movement, SR Ca2+ release, and muscle fiber contraction force. However, the mechanism is unknown. Here, we propose that JP-45 down regulation or ablation results in increased 11 subunit degradation meditated by an ubiquitin-proteasome proteolytic pathway.
Aim 2. To determine that age-dependent down regulation of JP-45 expression contributes to excitation- contraction uncoupling (ECU) in senescent mice. These experiments will test the hypothesis that JP45 is downregulates with senescence, leading to decreased DHPR11 expression and ECU. We created a JP-45- viral construct targeted exclusively to skeletal muscle, which can either prevent or restore age-dependent down regulation of JP-45 and, hence, DHPR11 down regulation, rescuing the aging ECC phenotype.
Aim 3. To demonstrate that age-dependent decrease in JP-45 expression contributes to reduced single intact muscle fiber specific force without affecting contractile myofilament sensitivity to Ca2+. In the same single fiber, first intact and then skinned, we will test voltage-dependent and independent properties, respectively, to answer the following questions: (1) Can JP-45 rescue age-dependent loss in contraction specific force? (2) Can it rescue decreases in peak intracellular Ca2+ mobilization with aging? (3) Is the decrease in fiber specific force a consequence of changes in contractile myofilament sensitivity to Ca2+? Aim 4. To demonstrate that JP-45 gene transcription declines with aging, that insulin-like growth factor-1 (IGF-1) regulates JP-45 gene transcription and that IGF-1-induced prevention or restoration of the decline in DHPR 11 subunit expression in aging skeletal muscle requires JP-45. We propose that: (1) JP-45 gene transcription decreases with aging, (2) IGF-1 regulates JP-45 gene transcription, and (3) IGF-1- induced 11 subunit upregulation is precluded by age-dependent JP-45 down regulation and JP-45 KO, supporting the theory that JP-45 protects 11 subunits from poly-ubiquitination and proteasome degradation. We will test this concept using S1S2, a transgenic mouse model that over-expresses IGF-1 in skeletal muscle, crossbred with JP-45KO mice or an IGF-1bidir viral vector.

Public Health Relevance

The growth of the aging population is a world-wide phenomenon. A better understanding of the decline in skeletal muscle molecular structure and function will allow more rationale interventions aimed at improving physical performance and independence in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG015820-14
Application #
8223261
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Williams, John
Project Start
1998-07-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
14
Fiscal Year
2012
Total Cost
$286,840
Indirect Cost
$91,764
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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