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RECRUITMENT OF SKELETAL MUSCLE BASED ON NON-SHIVERING THERMOGENESIS IN HEALTH AND DISEASE

Award Number: R01DK098240
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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DESCRIPTION (provided by applicant): Increasing evidence suggests that in addition to brown adipose tissue (BAT), skeletal muscle is an important site for Nonshivering thermogenesis (NST). Although several studies have suggested that SR Ca2+ cycling may play a role in muscle thermogenesis, the molecular details were not known. Studies from our laboratory and others have shown that Sarcolipin (SLN), a regulator of SR Ca2+ ATPase (SERCA), can bind to SERCA in the presence of Ca2+ and promote uncoupling of SERCA and increase ATP hydrolysis. In the presence of SLN, SERCA becomes inefficient; transporting less than 2 mol Ca2+ per mol ATP, thereby increasing ATP hydrolysis and heat production. These studies hinted that SLN could play a role in muscle thermogenesis .To define the relevance of SLN in muscle, we took a genetic approach and recently showed that loss of SLN predisposes mice to develop hypothermia during acute cold exposure but reintroduction of SLN in the Sln-/- background fully restored muscle-based thermogenesis. In addition, when Sln-/- mice when fed on high fat diet (HFD) gained significantly more weight than WT controls, whereas WT mice fed on HFD were less obese but showed significant upregulation of SLN (3-4 fold) suggesting that SLN is recruited in diet induced thermogenesis. These novel findings, for the first time, suggest SLN is the missing link for enhancing SERCA dependent heat generation by uncoupling the pump and this mechanism is recruited to increase energy expenditure during diet overload. However the mechanistic details with regard to recruitment of muscle NST, SLN-mediated uncoupling of SERCA, and how SLN increases muscle metabolism and energetics are poorly understood. The research proposed in this application challenges current thinking that BAT alone is responsible for Nonshivering thermogenesis. It seeks to establish that muscle is an important site of NST and can replace/substitute for thermogenesis in animals where BAT is absent or nonfunctional. The revised proposal places a greater emphasis on understanding the mechanistic basis of muscle NST. The current proposal seeks to identify sub cellular mechanisms that lead to activation of SERCA/SLN based thermogenesis. In Aim 1, we will investigate the mechanism behind activation of muscle-based NST during cold exposure and determine if SLN can replace/substitute for loss of BAT (UCP1) function in mammals. In Aim 2, we will test the therapeutic relevance of SLN and determine if overexpression of SLN can protect against diet- induced obesity by increasing energy expenditure. Another important goal of this aim is to discover how SLN increases muscle metabolism, if this involves Ca2+ dependant signaling pathways. In Aim 3, we will identify the structural features (binding sites and residues) of SLN/SERCA interaction and determine how SLN interaction leads to uncoupling and increased ATP hydrolysis. The experiments proposed here will collectively establish that SLN/SERCA interaction is the mechanism for skeletal muscle based NST and their relevance to Tc and whole body energy metabolism. Most importantly they will provide a mechanistic basis to show that SLN alone but not Phospholamban binding to SERCA causes uncoupling of the SERCA pump. We suggest that a better understanding of muscle thermogenesis has broader implications to our overall understanding of muscle metabolism, energy expenditure and evidently obesity in mammals including humans. Identification of the molecular mechanisms behind muscle based NST is of paramount importance to humans, since this strategy could be exploited to increase energy expenditure in muscle, thereby providing newer targets for obesity treatment.


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: 2021 ( Subtotal = -$1 )
2021	2017	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	2/14/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1
														Subtotal = -$1

Issue Date FY: 2019 ( Subtotal = -$43,468 )
2019	2017	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/14/2019	NON-COMPETING CONTINUATION	-$184,264
2019	2017	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	6	3/13/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$21,313
2019	2017	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	6	4/8/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2017	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	3/13/2019	NON-COMPETING CONTINUATION	-$21,313
2019	2017	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	2/15/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$140,796
														Subtotal = -$43,468

Issue Date FY: 2017 ( Subtotal = $424,125 )
2017	2017	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/19/2017	NON-COMPETING CONTINUATION	$424,125
														Subtotal = $424,125

Issue Date FY: 2016 ( Subtotal = $424,125 )
2016	2016	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/16/2016	NON-COMPETING CONTINUATION	$424,125
														Subtotal = $424,125

Issue Date FY: 2015 ( Subtotal = $424,125 )
2015	2015	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	9/1/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$424,125
														Subtotal = $424,125

Issue Date FY: 2014 ( Subtotal = $334,950 )
2014	2014	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/25/2014	NON-COMPETING CONTINUATION	$334,950
														Subtotal = $334,950

Issue Date FY: 2013 ( Subtotal = $333,863 )
2013	2013	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/13/2013	NEW	$333,863
														Subtotal = $333,863

Grand Total All Awards = $1,897,719

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RECRUITMENT OF SKELETAL MUSCLE BASED ON NON-SHIVERING THERMOGENESIS IN HEALTH AND DISEASE

Award Number: R01DK098240

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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