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AGE-DEPENDENT REGULATION OF EXCITATION-CONTRACTION COUPLING

Award Number: R01AG015820
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/1998
PERIOD OF PERFORMANCE END DATE: 02/28/2015

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AGE-DEPENDENT REGULATION OF EXCITATION-CONTRACTION COUPLING - DESCRIPTION (provided by applicant): 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2013 ( Subtotal = $271,063 )
2013	2013	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	15	4/3/2013	NON-COMPETING CONTINUATION	$258,155
2013	2013	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	001	15	5/17/2013	NON-COMPETING CONTINUATION	$12,908
														Subtotal = $271,063

Issue Date FY: 2012 ( Subtotal = $286,840 )
2012	2012	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	14	2/21/2012	NON-COMPETING CONTINUATION	$286,840
														Subtotal = $286,840

Issue Date FY: 2011 ( Subtotal = $286,840 )
2011	2011	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	001	13	6/23/2011	NON-COMPETING CONTINUATION	$18,264
2011	2011	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	13	2/7/2011	NON-COMPETING CONTINUATION	$268,576
														Subtotal = $286,840

Issue Date FY: 2010 ( Subtotal = $298,418 )
2010	2010	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	12	3/3/2010	NON-COMPETING CONTINUATION	$298,418
														Subtotal = $298,418

Issue Date FY: 2009 ( Subtotal = $299,464 )
2009	2009	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	001	11	2/23/2009	COMPETING CONTINUATION	$299,464
2009	2007	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	10	2/23/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $299,464

Issue Date FY: 2007 ( Subtotal = $268,003 )
2007	2007	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	10	6/18/2007	NON-COMPETING CONTINUATION	$268,003
														Subtotal = $268,003

Issue Date FY: 2006 ( Subtotal = $276,008 )
2006	2006	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	9	6/8/2006	NON-COMPETING CONTINUATION	$276,008
														Subtotal = $276,008

Issue Date FY: 2005 ( Subtotal = $282,650 )
2005	2005	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	8	6/22/2005	NON-COMPETING CONTINUATION	$282,650
														Subtotal = $282,650

Issue Date FY: 2004 ( Subtotal = $282,650 )
2004	2004	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	7	6/1/2004	NON-COMPETING CONTINUATION	$282,650
														Subtotal = $282,650

Issue Date FY: 2003 ( Subtotal = $283,600 )
2003	2003	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	6	6/6/2003	COMPETING CONTINUATION	$283,600
														Subtotal = $283,600

Issue Date FY: 2002 ( Subtotal = $196,561 )
2002	2002	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Aging Research	000	5	6/21/2002	NON-COMPETING CONTINUATION	$196,561
														Subtotal = $196,561

Issue Date FY: 2001 ( Subtotal = $191,636 )
2001	2001	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Aging Research	000	4	5/17/2001	NON-COMPETING CONTINUATION	$191,636
														Subtotal = $191,636

Issue Date FY: 2000 ( Subtotal = $186,857 )
2000	2000	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Aging Research	000	3	7/24/2000	NON-COMPETING CONTINUATION	$186,857
														Subtotal = $186,857

Issue Date FY: 1999 ( Subtotal = $182,217 )
1999	1999	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Aging Research	000	2	7/6/1999	NON-COMPETING CONTINUATION	$182,217
														Subtotal = $182,217

Issue Date FY: 1998 ( Subtotal = $177,712 )
1998	1998	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Aging Research	000	1	6/19/1998	NEW	$177,712
														Subtotal = $177,712

Grand Total All Awards = $3,770,519

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AGE-DEPENDENT REGULATION OF EXCITATION-CONTRACTION COUPLING

Award Number: R01AG015820

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/1998

PERIOD OF PERFORMANCE END DATE: 02/28/2015

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