Sarcopenia of aging is rapidly emerging as a major cause of many metabolic disorders and disabilities of increasing elderly population in our society. The current proposal investigates the effect of aging on muscle mitochondria which has substantial impact on both metabolic and mechanical function.
In Specific Aim 1 we will test a hypothesis that muscle mitochondrial ATP production decreases with age in three generations of women who inherit the same mitochondrial genome. We will also determine if stimulation of mitochondrial function by insulin and amino acids is reduced in older people. The phosphorylation of key proteins in signaling pathway for muscle protein synthesis will also be determined to detect any age-related defects. We will determine if oxidative damage increases with age and whether mitochondrial DNA copy numbers, mRNA levels of mitochondrial proteins, mitochondrial protein concentration, and activity of enzymes decrease in 12 families of three generations of women. The potential interaction of age and activity levels also will be investigated since alterations in activity levels have potential impact on mitochondrial function. Age-related changes in body composition may interact with age effect on mitochondria. Therefore, in Specific Aim 2 we will determine if obesity interacts with age on mitochondrial function. This is important because obesity is rapidly emerging as major public health problem especially in the aging population and may provide clues to the insulin resistance in aging. We have shown that amino acids have a stimulatory effect on muscle mitochondrial gene transcripts and functions but the impact of increasing protein intake on muscle mitochondrial functions remain to be defined. Therefore in Specific Aim 3 we will determine whether increasing the dietary protein content for 10 days enhances muscle mitochondrial functions and whether the response is similar in young and older people. The proposed studies will integrate information gathered from studies on mitochondrial DNA, gene transcript levels, protein concentrations and synthetic rates and metabolic changes to understand the underlying mechanisms of altered functions in aging muscle. Besides this primary objective, additional information on nuclear encoded proteins and gene transcript levels, and key proteins involved in signaling for muscle protein synthesis will also be obtained to better interpret the results on muscle mitochondria and to develop new hypotheses and approaches to understand the causes of sarcopenia of aging. These studies to understand the impact of age on muscle, may offer insights in to the agerelated changes in other predominant post-mitotic tissues such as brain and heart. Hopefully, the proposed studies and our continued commitment to further advance technology to test the emerging hypotheses from our ongoing research ensure substantial advance in our understanding of the biology of aging muscle.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG009531-15
Application #
7434536
Study Section
Special Emphasis Panel (ZRG1-ASG (01))
Program Officer
Dutta, Chhanda
Project Start
1993-04-15
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
15
Fiscal Year
2008
Total Cost
$576,867
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Robinson, Matthew M; Lowe, Val J; Nair, K Sreekumaran (2018) Increased Brain Glucose Uptake After 12 Weeks of Aerobic High-Intensity Interval Training in Young and Older Adults. J Clin Endocrinol Metab 103:221-227
Robinson, Matthew M; Dasari, Surendra; Konopka, Adam R et al. (2017) Enhanced Protein Translation Underlies Improved Metabolic and Physical Adaptations to Different Exercise Training Modes in Young and Old Humans. Cell Metab 25:581-592
Lalia, Antigoni Z; Dasari, Surendra; Johnson, Matthew L et al. (2016) Predictors of Whole-Body Insulin Sensitivity Across Ages and Adiposity in Adult Humans. J Clin Endocrinol Metab 101:626-34
Ryan, Zachary C; Craig, Theodore A; Folmes, Clifford D et al. (2016) 1?,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells. J Biol Chem 291:1514-28
Hebert, Sadie L; Marquet-de Rougé, Perrine; Lanza, Ian R et al. (2015) Mitochondrial Aging and Physical Decline: Insights From Three Generations of Women. J Gerontol A Biol Sci Med Sci 70:1409-17
Irving, Brian A; Lanza, Ian R; Henderson, Gregory C et al. (2015) Combined training enhances skeletal muscle mitochondrial oxidative capacity independent of age. J Clin Endocrinol Metab 100:1654-63
Johnson, Matthew L; Irving, Brian A; Lanza, Ian R et al. (2015) Differential Effect of Endurance Training on Mitochondrial Protein Damage, Degradation, and Acetylation in the Context of Aging. J Gerontol A Biol Sci Med Sci 70:1386-93
Irving, Brian A; Carter, Rickey E; Soop, Mattias et al. (2015) Effect of insulin sensitizer therapy on amino acids and their metabolites. Metabolism 64:720-8
Jedrychowski, Mark P; Wrann, Christiane D; Paulo, Joao A et al. (2015) Detection and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry. Cell Metab 22:734-740
Walrand, Stephane; Short, Kevin R; Heemstra, Lydia A et al. (2014) Altered regulation of energy homeostasis in older rats in response to thyroid hormone administration. FASEB J 28:1499-510

Showing the most recent 10 out of 79 publications