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 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.

• 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.

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 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 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 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.