Background: Sarcopenia is characterized by loss of muscle mass and weakness, leading to frailty, and impaired mobility. Prolonged muscle disuse, as occurs during hospitalization and bed rest, can accelerate the progression sarcopenia. Sarcopenia and its related co-morbidities are an enormous public health problem in the U.S. However, the mechanisms underlying sarcopenia have not been elucidated. Elevated muscle oxidative stress inhibits protein synthesis and increases protein breakdown, and has been identified as a mediator of muscle atrophy during disuse. While the source of oxidative stress during muscle atrophy has not been identified, reactive oxygen species (ROS) produced by mitochondria may play a role. The regulators of ROS production during prolonged muscle inactivity remains largely unknown. However, evidence suggests that the muscle lipid ceramide may play a role.
Aim :
The aim of this study is to determine the role of ceramide in mitochondrial ROS production and muscle atrophy in the context of aging and disuse. Methods: A hind limb model will be used to induce muscle atrophy in young and old mice. By specifically manipulating either ceramide content (myriocin treatment, DES-1 KO) or H2O2 (mCAT over-expression) within skeletal muscle using different experimental paradigms, we will be able to more carefully discern their roles in disuse atrophy. Muscle performance, including fatigability and maximal strength will be determined, as ceramide has also been shown to mediate fatigue and loss of strength. We will recruit sarcopenic low physically functioning and non-sarcopenic high physically functioning elderly individuals to define the relationships between muscle mass, function and muscle biopsy-derived ceramide species, and mitochondrial bioenergetics. Significance: The proposed studies will provide, for the first time, novel translational evidence i both animals and humans that intramyocellular ceramides contribute to mitochondrial ROS production, sarcopenia and loss of physical function.

Public Health Relevance

Sarcopenia and the compounding catabolic effects of bed rest during hospitalization contribute to significant morbidity and mortality in the growing elderly population. Evidence indicates that muscle energetics and lipid metabolism may be implicated in muscle atrophy and loss of contractile function in the elderly. The overarching goal of this study is to determine the contribution of specific muscle lipids and mitochondria dysfunction in sarcopenia and muscle atrophy caused by disuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG044437-02
Application #
8727434
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Williams, John
Project Start
2013-09-01
Project End
2017-05-31
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$129,592
Indirect Cost
$9,599
Name
Florida Hospital
Department
Type
DUNS #
824843312
City
Orlando
State
FL
Country
United States
Zip Code
32803
Distefano, Giovanna; Standley, Robert A; Zhang, Xiaolei et al. (2018) Physical activity unveils the relationship between mitochondrial energetics, muscle quality, and physical function in older adults. J Cachexia Sarcopenia Muscle 9:279-294
Gonzalez-Freire, Marta; Scalzo, Paul; D'Agostino, Jarod et al. (2018) Skeletal muscle ex vivo mitochondrial respiration parallels decline in vivo oxidative capacity, cardiorespiratory fitness, and muscle strength: The Baltimore Longitudinal Study of Aging. Aging Cell 17:
Stanford, Kristin I; Lynes, Matthew D; Takahashi, Hirokazu et al. (2018) 12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake. Cell Metab 27:1111-1120.e3
Zhang, Xiaolei; Trevino, Michelle B; Wang, Miao et al. (2018) Impaired Mitochondrial Energetics Characterize Poor Early Recovery of Muscle Mass Following Hind Limb Unloading in Old Mice. J Gerontol A Biol Sci Med Sci 73:1313-1322
Distefano, Giovanna; Standley, Robert A; Dubé, John J et al. (2017) Chronological Age Does not Influence Ex-vivo Mitochondrial Respiration and Quality Control in Skeletal Muscle. J Gerontol A Biol Sci Med Sci 72:535-542
Lee, Samuel; Leone, Teresa C; Rogosa, Lisa et al. (2017) Skeletal muscle PGC-1? signaling is sufficient to drive an endurance exercise phenotype and to counteract components of detraining in mice. Am J Physiol Endocrinol Metab 312:E394-E406
Gusdon, Aaron M; Callio, Jason; Distefano, Giovanna et al. (2017) Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice. Exp Gerontol 90:1-13
Fabbri, Elisa; Yang, An; Simonsick, Eleanor M et al. (2016) Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54-96 years from the Baltimore Longitudinal Study of Aging. Aging Cell 15:825-31
Santanasto, Adam J; Coen, Paul M; Glynn, Nancy W et al. (2016) The relationship between mitochondrial function and walking performance in older adults with a wide range of physical function. Exp Gerontol 81:1-7
Coen, Paul M; Goodpaster, Bret H (2016) A role for exercise after bariatric surgery? Diabetes Obes Metab 18:16-23

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