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Mitochondria and calcium signaling in skeletal muscle

Award Number: R01AR053933
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/19/2008
PERIOD OF PERFORMANCE END DATE: 08/31/2014

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Mitochondria and calcium signaling in skeletal muscle - DESCRIPTION (provided by applicant): Ca2+ controls numerous cellular processes in skeletal muscle and alterations in Ca2+ homeostasis are associated with human diseases such as Duchenne Muscular Dystrophy (DMD), Malignant Hyperthermia (MH) and Central Core Disease (CCD). Defining the molecular mechanisms regulating intracellular Ca2+ signaling is a crucial step for developing new therapeutic interventions in these myopathies. The release of Ca2+ from sarcoplasmic reticulum (SR) via Ca2+ release channels (ryanodine receptors, RyRs) is a key step in skeletal muscle excitation-contraction coupling (ECC). It is triggered through a direct interaction of the plasmalemmal voltage sensors with RyRs and it is thought to be amplified by Ca2+-induced Ca2+ release (CICR), manifest as Ca2+ sparks. However, mature mammalian muscle does not display Ca2+ sparks during physiological ECC but it develops spontaneous spark activity under various pathophysiological conditions. The molecular events that lead to Ca2+ spark generation in mammalian muscle are unknown. Understanding these mechanisms is a prerequisite to prevent changes in Ca2+ homeostasis associated with a number of human muscle diseases. Our data suggest that reactive oxygen and nitrogen species (ROS/RNS) and mitochondria are key regulators of intracellular Ca2+ signaling in skeletal muscle. They have led us to the following hypotheses: 1). Under physiological conditions, the appearance of sparks is suppressed by reduced cytosolic environment, which maintains a low activity of RyR1, and by mitochondrial Ca2+ uptake. 2). Increased cytosolic Ca2+ levels promote ROS/RNS production through mitochondrial Ca2+ overload and/or stimulation of ROS/RNS production by other cellular sources. 3). ROS/RNS stimulate spark production by enhancing the Ca2+ release activity of RyR1 and/or by inhibiting mitochondrial Ca2+ uptake. 4). Cytosolic Ca2+ levels are elevated in MH due to SR Ca2+ leak, and in DMD due to increased Ca2+ influx. In both disorders, the outcome of increased cytosolic Ca2+ is: a) enhanced ROS/RNS production b) oxidative modification of RyR1, c) enhanced Ca2+ sensitivity of the modified RyR1 and d) the appearance of Ca2+ sparks. To test these hypotheses, we will carry out the following Specific Aims using electrophysiological methods and state-of-the-art imaging techniques (single and two-photon confocal imaging, digital photometry, UV-laser flash photolysis of caged compounds). We propose to: 1). Determine the mechanisms connecting cytosolic Ca2+ signals, mitochondrial Ca2+ uptake and ROS/RNS generation in muscle under physiological conditions. 2). Define how altered ROS/RNS generation affect cellular Ca2+ homeostasis in muscle from MH-susceptible and mdx mice (a mice model of DMD).


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: 2014 ( Subtotal = $0 )
2014	2012	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	1/10/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$21,805
2014	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/10/2014	NON-COMPETING CONTINUATION	$21,805
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2012	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	9/18/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$246,220
2013	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	9/18/2013	NON-COMPETING CONTINUATION	-$246,220
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $326,177 )
2012	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	8/17/2012	NON-COMPETING CONTINUATION	$326,177
														Subtotal = $326,177

Issue Date FY: 2011 ( Subtotal = $326,177 )
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	8/22/2011	NON-COMPETING CONTINUATION	$326,177
														Subtotal = $326,177

Issue Date FY: 2010 ( Subtotal = $339,768 )
2010	2010	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/24/2010	NON-COMPETING CONTINUATION	$339,768
														Subtotal = $339,768

Issue Date FY: 2009 ( Subtotal = $343,200 )
2009	2009	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	8/28/2009	NON-COMPETING CONTINUATION	$343,200
2009	2008	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/28/2009	NEW	$0
														Subtotal = $343,200

Issue Date FY: 2008 ( Subtotal = $330,880 )
2008	2008	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/16/2008	NEW	$330,880
														Subtotal = $330,880

Grand Total All Awards = $1,666,202

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Mitochondria and calcium signaling in skeletal muscle

Award Number: R01AR053933

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/19/2008

PERIOD OF PERFORMANCE END DATE: 08/31/2014

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