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Muscle Mitochondrial Pyruvate Carrier Disruption Alters Amino Acid Metabolism to Maintain Muscle Mass During Recovery from Obesity

Award Number: F30DK127845
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Project Summary/Abstract Type 2 diabetes (T2D) is a widespread metabolic disorder that is characterized by insulin resistance and hyperglycemia. Obesity, the excess accumulation of fat mass, is a major T2D risk factor and is strongly associated with insulin resistance in skeletal muscle and liver, resulting in less glucose uptake by both organs. Reduced muscle glucose uptake contributes to chronic hyperglycemia and is further exacerbated by excessive hepatic gluconeogenesis. Because skeletal muscle is the largest tissue depot available for glucose disposal, sarcopenia, the loss of skeletal muscle mass, also contributes to hyperglycemia. Though obesity and sarcopenia are key factors that contribute to the pathogenesis of T2D, current therapies address insulin availability or sensitivity without addressing the underlying imbalance between fat and muscle mass. Disruption of the skeletal muscle mitochondrial pyruvate carrier (MPC) increases insulin sensitivity and accelerates fat loss with complete muscle mass sparing in mice recovering from obesity. Thus, modulating skeletal muscle pyruvate metabolism may be useful for treating altered body composition as a T2D root cause. Our previous work has focused on understanding how muscle-specific MPC disruption increases fat oxidation. However, how skeletal muscle MPC disruption maintains lean mass during fat mass loss is still not understood. Therefore, the overall goal of this proposal is to understand how disrupting skeletal muscle mitochondrial pyruvate uptake spares muscle mass during recovery from obesity. Based on our preliminary data, the central hypothesis of this proposal is that muscle MPC disruption leads to muscle mass sparing during recovery from obesity through: 1) a whole-body mechanism of altered substrate exchange between muscle and liver that spares nitrogen for muscle mass; and 2) a unique, MPC disruption-dependent, muscle-autonomous mechanism of nitrogen retention. Experiments for specific aim 1 will test the hypothesis that muscle MPC disruption increases Cori Cycling, the exchange of lactate and glucose between muscle and liver, which spares nitrogen for skeletal muscle protein and amino acid synthesis during weight loss and recovery from obesity. Experiments for specific aim 2 will test the hypothesis that skeletal muscle MPC disruption increases aspartate and branched-chain amino acid (BCAA) availability that leads to maintenance of myocellular protein content. This research is significant because completion will provide mechanistic information on a way to alter skeletal muscle metabolism that may inform treatment of obesity and sarcopenia contributing to T2D. This research is novel because it addresses new concepts in cellular and systemic nitrogen handling.


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: 2023 ( Subtotal = $36,119 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/24/2023	NON-COMPETING CONTINUATION	$36,119
														Subtotal = $36,119

Issue Date FY: 2022 ( Subtotal = $37,439 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/5/2022	NON-COMPETING CONTINUATION	$37,440
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/20/2022	NON-COMPETING CONTINUATION	-$1
														Subtotal = $37,439

Issue Date FY: 2021 ( Subtotal = $36,723 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	6/8/2021	NEW	$0
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/8/2021	NEW	$36,723
														Subtotal = $36,723

Grand Total All Awards = $110,281

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Muscle Mitochondrial Pyruvate Carrier Disruption Alters Amino Acid Metabolism to Maintain Muscle Mass During Recovery from Obesity

Award Number: F30DK127845

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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