With age we lose muscle mass at approximately 1-2% per year past the age of 50. This age-related muscle atrophy, termed sarcopenia, is relatively poorly understood, impacts the severity of frailty, and has significant effects on individual health and quality of life. While the specific mechanisms underlying sarcopenia are unknown, energy deficits in aging muscle have been strongly implicated as precursors to muscle atrophy and apoptotic cell death, suggesting that mitochondrial dysfunction may play a significant role in the progression of sarcopenia. Previous studies have shown decreased mitochondrial oxidative functional capacity with age, which was associated with increased oxidant production in mitochondrial complex I and complex III. However, characterization of age-related changes to skeletal muscle mitochondria has been complicated by the realization that two distinct populations of mitochondria exist: interfibrillar mitochondria (IFM), which are found in parallel rows between the myofibrils, and subsarcolemmal mitochondria (SSM), which are located beneath the plasma membrane. IFM are likely the primary source of ATP during muscle contraction, and we believe they are therefore more likely to accumulate oxidative damage with age. Our central hypothesis is that IFM exhibits a greater free radical leak in complex I and III and oxidative damage, and that this is responsible for increased mitochondrial dysfunction, skeletal muscle atrophy and decreased contractile function, all of which could be amplified in type II muscle compared with type I muscle. In the proposed experiments, we will obtain young, mid-aged and old rats, determine skeletal muscle contractile function, apoptosis and the extent of sarcopenia in type I and type II muscle, and we will isolate IFM and SSM from both fiber types and measure key parameters of bioenergetics. In a second series of experiments, we will examine the same factors and variables, but with addition of two well-characterized interventions that have been shown to extend life span: calorie restriction and life-long wheel running, to determine the mechanisms by which these interventions significantly ameliorate age-related oxidative damage, mitochondrial dysfunction and muscle loss. This could provide evidence for the mechanisms underlying sarcopenia, and may also provide the first direct evidence that mitochondrial dysfunction has a negative impact on muscle cell function and contractility.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG017994-10S1
Application #
8536447
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Williams, John
Project Start
2000-08-01
Project End
2013-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$57,500
Indirect Cost
$18,909
Name
University of Florida
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Picca, Anna; Sirago, Giuseppe; Pesce, Vito et al. (2018) Administration of Enalapril Started Late in Life Attenuates Hypertrophy and Oxidative Stress Burden, Increases Mitochondrial Mass, and Modulates Mitochondrial Quality Control Signaling in the Rat Heart. Biomolecules 8:
Chimienti, Guglielmina; Picca, Anna; Sirago, Giuseppe et al. (2018) Increased TFAM binding to mtDNA damage hot spots is associated with mtDNA loss in aged rat heart. Free Radic Biol Med 124:447-453
Picca, Anna; Pesce, Vito; Sirago, Giuseppe et al. (2016) ""What makes some rats live so long?"" The mitochondrial contribution to longevity through balance of mitochondrial dynamics and mtDNA content. Exp Gerontol 85:33-40
Picca, Anna; Pesce, Vito; Fracasso, Flavio et al. (2014) A comparison among the tissue-specific effects of aging and calorie restriction on TFAM amount and TFAM-binding activity to mtDNA in rat. Biochim Biophys Acta 1840:2184-91
Picca, Anna; Fracasso, Flavio; Pesce, Vito et al. (2013) Age- and calorie restriction-related changes in rat brain mitochondrial DNA and TFAM binding. Age (Dordr) 35:1607-20
Joseph, Anna-Maria; Adhihetty, Peter J; Wawrzyniak, Nicholas R et al. (2013) Dysregulation of mitochondrial quality control processes contribute to sarcopenia in a mouse model of premature aging. PLoS One 8:e69327
Fletcher, Quinn E; Selman, Colin; Boutin, Stan et al. (2013) Oxidative damage increases with reproductive energy expenditure and is reduced by food-supplementation. Evolution 67:1527-36
Picca, Anna; Pesce, Vito; Fracasso, Flavio et al. (2013) Aging and calorie restriction oppositely affect mitochondrial biogenesis through TFAM binding at both origins of mitochondrial DNA replication in rat liver. PLoS One 8:e74644
Aris, John P; Alvers, Ashley L; Ferraiuolo, Roy A et al. (2013) Autophagy and leucine promote chronological longevity and respiration proficiency during calorie restriction in yeast. Exp Gerontol 48:1107-19
Joseph, Anna-Maria; Malamo, Angelina G; Silvestre, Jason et al. (2013) Short-term caloric restriction, resveratrol, or combined treatment regimens initiated in late-life alter mitochondrial protein expression profiles in a fiber-type specific manner in aged animals. Exp Gerontol 48:858-68

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