Sarcopenia, a progressive loss of muscle mass and strength associated with aging, is present in 25% of older individuals. Obesity is also very common in this age group and both conditions lead to increased disability, morbidity and mortality. Their combination is termed sarcopenic obesity and is associated with the highest risks of disability, mortality and increased healthcare costs. Despite its relevance, treatments for sarcopenic obesity are not available and the molecular mechanisms leading to this condition are incompletely understood. Ghrelin, the endogenous ligand for the GHSR-1a receptor, is an orexigenic hormone that regulates muscle and fat mass. We recently showed that ghrelin deletion is sufficient to prevent sarcopenic obesity in older mice. It attenuates the decrease in pAMPK and increases the number of type IIa (oxidative) muscle fibers, while also preventing obesity. Also, we have recently shown that ghrelin exerts its effects in muscle and in adipose tissue, at least in part, independently of the GHSR-1a. However, the mechanisms mediating these effects are incompletely understood. The overall goals of this proposal are to characterize the mechanisms mediating the role of ghrelin and its receptor (GHSR-1a) in sarcopenic obesity, and to evaluate the potential for GHSR-1a antagonism as a therapeutic approach in this setting. We hypothesize that in a rodent model of age- related sarcopenic obesity: 1) Ghrelin induces skeletal muscle dysfunction by: a) Causing mitochondrial dysfunction and fiber type distribution changes, and b) Modulating fatty acid metabolism and ectopic lipid deposition; 2) Ghrelin induces fat accumulation by modulating food intake, thermogenesis, and fatty acid metabolism in adipose tissue, and 3) GHSR-1a antagonism/deletion will partially prevent sarcopenic obesity by upregulating AMPK-dependent pathways that regulate fiber type distribution in muscle and mitochondrial function and lipid metabolism in skeletal muscle and adipose tissue.
The specific aims are: 1) Characterize the mechanisms mediating the effects of ghrelin in muscle in sarcopenic obesity. Young (8-month old), middle age (18-month old) and old (28-month old) adult ghrelin WT&KO mice will be evaluated for body composition, food intake, locomotor activity and muscle performance. Muscle mass, fiber type and markers of AMPK activation, mitochondrial function, fatty acid metabolism, and lipid storage will be evaluated in muscles. The effect of chronic ghrelin administration, and pair-feeding will also be tested. 2) Determine the mechanisms mediating the effects of ghrelin on adiposity and adipocyte function in sarcopenic obesity. Young, middle age and old adult ghrelin WT and KO mice will be evaluated for energy expenditure, body composition, food intake and locomotor activity. Molecular mediators of thermogenesis, mitochondrial function, AMPK activation and lipid metabolism will be probed in white and brown fat pads. The effect of chronic ghrelin administration, and pair-feeding will also be tested. 3) Establish the extent to which GHSR-1a mediate the effects of ghrelin. Young, middle age and old adult GHSR-1a WT and KO mice will be evaluated for body composition, food intake, locomotor activity, muscle performance and energy expenditure. Fiber typing and molecular markers in muscle and fat will be studied as indicated in aims 1 and 2 above. The effect of chronic ghrelin administration in GHSR-1a WT and KO, and pharmacological inhibition of GHSR-1a (using the GHSR-1a antagonist HM04) in ghrelin WT and KO also will be tested. To determine the role of AMPK in this setting, the effects of HM04 will also be tested in WT and AMPK?2i transgenic mice that express the inactive form AMPK? in skeletal muscle. Characterizing the mechanisms mediating the effects of ghrelin and GHSR-1a is novel and relevant because ghrelin, GHSR-1a agonists and antagonists are in clinical development. A better understanding of their mechanisms of action will allow us to develop novel therapies for sarcopenic obesity.

Public Health Relevance

The loss of muscle mass and function associated with obesity is known as ?sarcopenic obesity?. This condition is very common in the elderly and is over-represented in the veteran population, reducing functionality and quality of life, and increasing mortality. We have generated exciting preliminary data suggesting that the hormone ghrelin and its receptor GHSR-1a may play a role in the development of ?sarcopenic obesity?. This proposal will determine their effects and mechanisms of action in this setting. The results generated by these studies are expected to help us develop new treatments for this condition; thereby improving quality of life by allowing veterans to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX002807-06
Application #
9887510
Study Section
Special Emphasis Panel (ZRD1)
Project Start
2015-10-01
Project End
2023-09-30
Budget Start
2019-10-01
Budget End
2020-09-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
VA Puget Sound Healthcare System
Department
Type
DUNS #
020232971
City
Seattle
State
WA
Country
United States
Zip Code
98108
Guillory, Bobby; Jawanmardi, Nicole; Iakova, Polina et al. (2018) Ghrelin deletion protects against age-associated hepatic steatosis by downregulating the C/EBP?-p300/DGAT1 pathway. Aging Cell 17:
Anderson, Lindsey J; Tamayose, Jamie M; Garcia, Jose M (2018) Use of growth hormone, IGF-I, and insulin for anabolic purpose: Pharmacological basis, methods of detection, and adverse effects. Mol Cell Endocrinol 464:65-74
Maldonado, Maria; Molfese, David L; Viswanath, Humsini et al. (2018) The habenula as a novel link between the homeostatic and hedonic pathways in cancer-associated weight loss: a pilot study. J Cachexia Sarcopenia Muscle 9:497-504
Anderson, Lindsey J; Liu, Haiming; Garcia, Jose M (2017) Sex Differences in Muscle Wasting. Adv Exp Med Biol 1043:153-197
Zhang, Guohua; Liu, Zhelong; Ding, Hui et al. (2017) Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways. Sci Rep 7:2273
Anderson, Lindsey J; Albrecht, Eliette D; Garcia, Jose M (2017) Update on Management of Cancer-Related Cachexia. Curr Oncol Rep 19:3
Guillory, Bobby; Chen, Ji-An; Patel, Shivam et al. (2017) Deletion of ghrelin prevents aging-associated obesity and muscle dysfunction without affecting longevity. Aging Cell 16:859-869
Graf, Solomon A; Garcia, Jose M (2017) Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome: design, development, and potential place in therapy. Drug Des Devel Ther 11:2325-2331
Garcia, Jose M (2017) What is next after anamorelin? Curr Opin Support Palliat Care 11:266-271
Erickson, Megan; Braun, Katie; List, Riesa et al. (2016) Evaluation of US Veterans Nutrition Education for Diabetes Prevention. J Nutr Educ Behav 48:538-543.e1

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