Projects

Aging

Aging is a deteriorative process of the biological system that gradually loses regeneration ability whereas catabolic pathways take over. Free Radical Theory of Aging postulates that aging is caused by the accumulation of oxidatively degraded macromolecules results from  reactive oxygen species (ROS)  throughout the life span. Supplementation of  antioxidants  has been regarded beneficial to attenuate aging effects. However, recent research challenges this theory and even provides evidence that ROS stimulates the organisms against aging process.

Our research focuses on the role of ROS and antioxidant system in aging. We are particularly interested in how physical exercise and muscle inactivity modulate progression of aging in skeletal muscle and heart, such as  sarcopenia . Our research points to the importance of exercise in regenerating muscle metabolic function and maintaining antioxidant defense so as to keep vitality of the organ during aging.

Sarcopenia

Sarcopenia is a term to describe the progressive loss of muscle weight, fine structure and force generation over age, especially passing 60. Numerous theories can partially explain the mechanism of sarcopenia, but most recent literature emphasizes a disorder of  cell signaling , leading to decreased balance of biosynthesis and degradation. Decreases function of mitochondria and gene expression are especially prominent. We are interested in both the biomechanism and prevention of sarcopenia.

Related publications

  • Ji, L.L and C. Kang. Role of PGC-1α in the Etiology of Sarcopenia. Gerontol. 61: 139-148, 2015.
  • Ji, L. L. Redox Signaling in Skeletal Muscle:. Effects of Aging and Exercise Am. J. Physiol. (Adv. Physiol. Edu.) (doi:10.1152/advan.00106.2014.)
  • Kang, C., E. Chung, and L. L. Ji. Exercise training stimulates PGC-1 and mitochondrial biogenic pathway in skeletal muscle of aged rats. Exp. Gerontol. 48: 1343-1350, 2013.
  • Powers, S.K., L.L. Ji, A.N. Kavazis, and M.J. Jackson. Reactive oxygen species: impact on skeletal muscle. Comprehensive Physiol. 1(2) 941–969, 2011.
  • Ji, L. L. , J. R. Dickman, C. Kang, and R. Koenig. Exercise-induced Hormesis may help healthy aging. Dose-Response 28: 73-79, 2010.
  • Ji, L. L. Exercise-induced modulation of antioxidant defense. Ann. N.Y. Acad. Sci. 959: 82-92, 2002.

Antioxidants

Antioxidants can be classified into enzymes, vitamins, small molecule antioxidants and plant phytochemicals . They either scavenge ROS or convent more harmful species to a lesser one. Some antioxidants such as vitamin E. C. can only be obtained via diet; some trace elements such as copper, zink, manganese and selenium are essential in the formation of antioxidant enzymes. One of our primary interest is to study how antioxidant enzymes are regulated by exercise, nutrient intake, disease, and aging.

Phytochemicals

Phytochemicals are organic molecules in plants (vegetables, fruits, grain, herbs, etc.) that demonstrate biological functions useful to human. Ginsenoside ( ginseng ), resveratrol (grape), catechin (tea),isoflavon (soy) are known to most people. Recent research indicates that these compounds serve not only as antioxidants but properties such as DNA binding, anti-inflammation, cancer-inhibiting, just to list a few. Currently our lab is studying anti-inflammatory function of  avenanthramide , in oats and  oleocanthal  in olive oil, both at the gene level to explore their mechanism of action and in clinical trials to learn their efficacy in human.

Avenanthramides

Avenanthramides (AVA) are a group of diphenolic acids only found in oats. AVA have shown antioxidant anti-inflammatory and anti-atherogenic effects. These effects were shown to be derived from decreased NFκB activity. AVA is bioavailable to animal and human. Supplementation of AVA has been shown to inhibit plasma inflammatory markers induced by eccentric exercise.

Ginseng

Ginseng has demonstrated potent antioxidant function in vitro and in vivo that is largely attributed to the glycoside saponins (ginsenosides) content in the herb. Ginseng supplementation has been shown to reduce oxidative damage and increase antioxidant enzyme activities in numerous animal and human studies. We have shown that rats fed a diet fortified with ginseng had increased antioxidant enzyme activities and decreased protein oxidation in heart and skeletal muscles, and aged women supplemented with ginseng capsules daily increased plasma antioxidant capacity.

Related publications

  • Koenig, R., J. Dickman and L. L. Ji. Avenanthramides are Bioavailable and Accumulate in Hepatic, Cardiac, and Skeletal Muscle Tissue following Oral Gavage in Rats. J. Agr. Food Chem. 59:6438-43, 2011.
  • Dickman, J. R., R.T. Koenig, and L. L. Ji. American ginseng supplementation induces a mild oxidative stress in elderly women. J. Am. Coll. Nutr. 28:219-228, 2009.
  • Ji, L.L., D. Lay, E, Chung, Y. Fu, and D. M.. Peterson. Effects of avenanthramides on oxidant and antioxidant status in exercised rats. Nutr. Res. 23: 1579-1590, 2003.
  • Koenig, R, J. Dickman, C. Kang, and L. L. Ji. Avenathranmide Supplementation Attenuate Eccentric Exercise-induced Inflammation and Oxidative Stress in Young Women. Eur. J. Appl. Physiol. (DOI 10.1007/s00421-015-3244-3)
  • Fu, Y. and L. L. Ji. Chronic Ginseng Consumption Attenuates Age-Associated Oxidative Stress in Rats. J. Nutr. 133: 3603-3609, 2003.

Cell signaling

Cells communicate with each other via hormones, nerves and chemicals to reach synergistic functions such as growth, differentiation, metabolism, adaptation and self-programmed death (apoptosis). ROS have been found to play an important role in regulating the communications termed  redox signaling . Our group has studied several pathways deemed important in the maintenance and adaption of  antioxidants ,  mitochondria , anti-inflammation and  aging  in muscle and heart, such as  PGC-1α ,  MAP kinase ,  NFκB , Sirt, and FoxO. We are particularly interested in the effects of exercise, inactivity, aging and nutritional intervention on these signaling pathways. The adaptation of these systems are postulated as a phenomenon called  hormesis .

Redox signaling

Redox signaling is a process during which some stable ROS produced in the cell activate or inhibit pathways that regulate metabolism, gene expression, biodegradation, inflammation, and apoptosis in a reversible way. The actions are mostly through covalent modification of key enzyme moieties such as oxidation/reduction, phosphorylation, acetylation, etc. We have shown that muscle contractile and immobilization can significant impact on redox signaling of several pathways leading to functional up- or down-regulation.

MAP kinase

MAP kinase is a group of kinases involved in a wide range of cell functions such as growth, differentiation, metabolism and gene expression. Crosstalk of MAPK with other signaling pathways such as  PGC-1α  and  NFκB  is critical to confer many adaptations seen after acute and chronic exercise.

Hormesis

Hormesis is a biological concept which states that exposure to a low dose of a noxious or toxic agent can bring about results deemed beneficial to the long-term welfare of the organisms. Exercise produces ROS which could result in oxidative damage, but ROS also stimulates redox signaling and adaptation of metabolic and antioxidant function that make the muscle more resistant to ROS-induced detrimental effects. Thus, exercise has a hermetic effect to the body.

PGC-1α

PGC-1α is regarded a master transcription cofactor involved in mitochondrial biogenesis, dynamics, fuel selection, muscle fiber transformation, hypertrophy, antioxidant defense and many other aspects of metabolism. Both acute and chronic exercise can induce PGC-1α in muscle whereas transfecting an atrophying muscle with PGC-1α restores its morphological and functional integrity.

NFκB

NFκB) is a redox signaling pathway involved in the regulation of antioxidant, autophagy, apoptosis and inflammation. Its activation by oxidants, virus, toxin and UV light is required for many adaptions, but hyper-activation may counter the effects of  PGC-1α  and underlie the etiology of some disorders and diseases. Heavy exercise is known to activate NFκB due to increased ROS, whereas  PGC-1α  overexpression can inhibit NFκB.

Related publications

  • Ji, L. L. and Y. Zhang. Antioxidant and anti-inflammatory effects of exercise: role of redox signaling. Free Rad. Res. 48:3-11, 2014.
  • Feng, H., C. Kang, J. R. Dickman, R. Koenig, Awoyinka, Y. Zhang and L. L. Ji. Training-induced mitochondrial adaptation: role of peroxisome proliferator-activated receptor γ coactivator-1α, nuclear factor-κB and β-blockade. Exp. Physiol. 98:784-95, 2013.
  • Kang, C. and L. L. Ji. Muscle immobilization and remobilization downregulates PGC-1 signaling and the mitochondrial biogenesis pathway. J. Appl. Physiol. 115: 1618-1625, 2013.
  • Feng, H., C. Kang, J. R. Dickman, R. Koenig, Awoyinka, Y. Zhang and L. L. Ji. Training-induced mitochondrial adaptation: role of peroxisome proliferator-activated receptor γ coactivator-1α, nuclear factor-κB and β-blockade. Exp. Physiol. 98:784-95, 2013.
  • Kang, C., E. Chung, and L. L. Ji. Exercise training stimulates PGC-1 and mitochondrial biogenic pathway in skeletal muscle of aged rats. Exp. Gerontol. 48: 1343-1350, 2013.
  • Kang, C., C.A. Goodman, T. A. Hornberger, L. L. Ji. PGC-1α Over-expression by in vivo Transfection Attenuates Mitochondrial Deterioration of Skeletal Muscle Caused by Immobilization. FASEB J. (0892-6638/15/0029-0001)
  • Kang, C and L. L. Ji. Role of PGC-1α Signaling in Skeletal Muscle Health and Disease. Ann. N.Y. Acad. Sci. 1271:110-7, 2012.
  • Ji, L. L. , J. R. Dickman, C. Kang, and R. Koenig. Exercise-induced Hormesis may help healthy aging. Dose-Response 28: 73-79, 2010.
  • Gomez-Cabrera, M-C, J. Vina and L. L. Ji . Oxidants and Antioxidants Interplay during Exercise: Implication in Muscle Health. Physician Sports Med. 37: 116-123, 2009.
  • Kang C., K. M. O’Moore, J. R. Dickman and L. L. Ji. Exercise activation of muscle peroxisome proliferator-activated receptor-γ coactivator-1α signaling is redox sensitive. Free Rad. Biol. Med. 47: 1394-1400, 2009.
  • Ji, L. L. M-C. Gomez-Cabrera, and J. Vina. Role of Antioxidants in Muscle Health and Pathology. Infectious Disorders Special Issue. Infect. Disord. Drug Targets 9(4):428-444, 2009.
  • Ji, L. L. Z. Radak, and S. Goto. Exercise and hormesis: How the Cell Copes with Oxidative Stress Am. J. Pharmacol. Toxicol. 3 (1): 41-55, 2008.
  • Ji, L. L. Antioxidant signaling in skeletal muscle: a brief review. Exp. Gerontol. 42: 582-593, 2007.
  • Ji, L. L., M.C. Gomez-Cabrera and J. Vina. Role of nuclear factor κB and mitogen-activated protein kinase signaling in exercise-induced antioxidant enzyme adaptation. Appl. Physiol. Nutr. Metabol. 5:930-935, 2007.
  • Ji, L. L., M-C. Gomez-Cabrera and J. Vina. Exercise and hormesis: Activation of cellular signaling pathways. Ann. N. Y. Acad. Sci. 1067:425-435, 2006.
  • Gomez-Cabrera, M-C, C. Borras, G. Santangelo, F.V. Pallardó , J. Sastre, L. L. Ji and J. Vina. Decreasing xanthine oxidase mediated oxidative stress prevents useful cellular adaptations to exercise in rats. J. Physiol. (London) 567:113-120, 2005.
  • Ji, L. L., M-C. Gomez-Cabrera, N. Steinhafel, and J. Vina. Acute Exercise Activates Nuclear Factor (NF) B Signaling Pathway in Rat Skeletal Muscle. FASEB J. 18:1499-1506, 2004.

Mitochondria

Mitochondria is a vital organelle in the cell that controls fuel selection, energy metabolism, oxygen consumption, ROS/antioxidant balance and apoptosis. Mitochondrial volume and quality are regulated by  biogenesis ,  mitophagy , and  dynamics  via  redox signaling . We have a long-standing interest in studying mitochondrial properties in response to acute and chronic exercise, antioxidant intervention, certain diseases and aging.

Mitochondrial biogenesis

Mitochondrial biogenesis is regulated primarily by PGC-1α, a master cofactor required for synthesis and transport of most mitochondrial proteins, mitochondrial DNA proliferation, and antioxidant enzyme expression. Overexpresion of PGC-1α leads to transformation to more oxidative muscle fibers, higher oxidative capacity, greater fat utilization, fiber hypertrophy and greater resistance to oxidative stress and inflammation. Our lab has demonstrated that increased PGC-1α via DNA transfection can ameliorate muscle  atrophy caused by immobilization and this is accomplished by increased mitochondrial biogenesis and reduced  mitophagy .

Mitophagy

Mitophagy is a process during which non-functional and "old" mitochondria are targeted for degradation through a pathway called mitophagy-lysosomal system. Many enzymes are involved in the identification, labeling, ubiquitation and degradation of damaged mitochondria. Dysregulation is implicated in numerous cell functions and pathogenic conditions. We have demonstrated that muscle inactivity can enhance mitophagy, associated with oxidative stress and inflammation, whereas PGC-1α transfection can inhibit mitophagy in muscle disuse atrophy.

Mitochondrial dynamics

Mitochondrial dynamics defines morphological and ultrastructural changes in mitochondria regulated by fusion and fission. Thus, the organelle used to be considered “peanut shell” is actually a dynamic reticular network constantly changing it shape. We have studied the expression of several key proteins that regulate fusion and fission, such as Mfn1/2, Fis 1, Opa-1, and DRP. It is obvious that muscle activity has profound influence on these gene expressions which ultimately determine mitochondrial turnover and function.

Related publications

  • Li, H., W. Miao, J. Ma, Z. Xu, H. Bo, L. L. Ji, Y. Zhang. Mitochondrial stress triggers inflammatory response of myocardium via NLRP3 inflammasome activation during acute exercise. Oxid. Med. Cell. Longev. (Volume 2016, Article ID 1987149, 11 pages. http://dx.doi.org/10.1155/2016/1987149)
  • Kang, C., D. Yeo and L. L. Ji. PGC-1α Over-expression by in vivo transfection alters immobilization-induced mitophagy and mitochondrial dynamics in rat skeletal muscle. Free Rad. Biol. Med. (in press)
  • Ding H,, N. Jiang, H. Liu, X. Liu, D. Liu, F. Zhao, L. Wen, S. Liu , L. L. Ji, Yong, Zhang. Dynamic Response of mitochondrial fusion and fission protein gene expression to exercise in rat dkeletal muscle. Biochim. Biophys. Acta 1800: 250-256, 2010.
  • Bo H, Y. Zhang, L.L. Ji. Redefining the Role of Mitochondria in Exercise: a Dynamic Remodeling. Ann. N. Y. Aca. Sci. 1201: 121-128, 2010.