Yan Laboratory
Molecular
Exercise Physiology

Center for Skeletal Muscle Research
Robert M. Berne Cardiovascular Research Center
University of Virginia School of Medicine
409 Lane Road, MR4 - 6041A
Charlottesville, VA 22908
Phone: 434-982-4477
Fax: 434-982-3139
E-mail:
zhen.yan@virginia.edu

Research Topics in Yan Lab

Exercise benefits in protection against diseases
Exercise training is the most effective intervention against numerous diseases, including cancer, cardiovascular, metabolic and neurodegenerative diseases; however, the underlying mechanism for the benefits of exercise training is not fully understood. We have obtained data to show that an antioxidant protein, extracellular superoxide dismutase (EcSOD), is inducible in a nitric oxide (NO)-dependent manner in skeletal muscle. EcSOD is highly induced by exercise training in a mouse model of exercise. We test the hypothesis that endurance exercise training-induced EcSOD expression in skeletal muscle provides profound protection against oxidative damage in skeletal muscle and other peripheral tissues/organs. We are specifically interested in the roles of endurance exercise training-induced EcSOD expression in protection against catabolic muscle wasting induced by congenital heart failure, diabetic cardiomyopathy and multiple organ dysfunction syndrome induced by sepsis and trauma. The findings will also provide novel insights into the moledular mechanism by which regular exercise elicits profound protection against many other disease conditions, such as diabetes, atherosclerosis, heart failure and peripheral arterial disease.

Schematic illustration of the role of enhanced EcSOD expression in skeletal muscle in protection against diabetic cardiomyopathy (DCM) (Call et al. Circ Heart Fail, 2014)

Heterochronic parabiosis led to protection to wild type mice (WT) from EcSOD transgenic mice (TG) 6 hrs following LPS injection (50 mg/kg, i.p.)as shown by the lung floating in the fixative (preserved air space).

A working model for EcSOD-mediated protection against sepsis-induced multiple organ dysfunction syndrome (MODS) by reducing endothelial activation and inflammatory cell extravasation.

Publications (Key publications marked ****):
1. Koves TR, Li P, Akimoto T, An J, Slentz D, Ilkayeva O, Dohm GL, Yan Z, Newgard CB, Muoio DM. PGC-1α-mediated metabolic remodeling of skeletal muscle mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J. Biol. Chem. 2005; 280(39):33588-98. Full text (PDF)

2. Perrino C, Prasad SV, Mao L, Noma T, Yan Z, Kim HS, Smithies O, Rockman HA. Intermittent overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J. Clin. Invest. 2006; 116(6):1547-6. Full text (PDF)

3. ****Li P, Waters RE, Redfern SI, Zhang M, Mao L, Annex BH, Yan Z. Oxidative phenotype protects myofibers from pathological insults induced by chronic heart failure in mice. Am. J. Pathol. 2007; 170(2):599-608. Full text (PDF)

4. ****Yu Z, Li P, Zhang M, Hannink M, Stamler JS, Yan Z. Fiber type-specific nitric oxide protects oxidative myofibers against cachectic stimuli. PLoS One 3(5): e2086, 2008. Full text (PDF)

5. ****Ajijola OA, Dong C, Herderick E, Qi Ma, Goldschmidt-Clermont PJ, Yan Z. Voluntary running suppresses pro-inflammatory cytokines and bone marrow endothelial progenitor cell levels in Apolipoprotein E-deficient mice. Antioxid Redox Signal 11:15-23, 2008. Full text (PDF)

6. Hazarika S, Angelo M, Li Y, Aldrich AJ, Odronic S, Yan Z, Stamler JS, Annex BH. Myocyte Specific Overexpression of Myoglobin Impairs Angiogenesis Following Hind-limb Ischemia. Arterioschlerosis, Thrombosis, and Vascular Biology 28:2144-50, 2008. Full text (PDF)

7. ****McClung JM, Judge AR, Powers SK, Yan Z. p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting. Am J Physiol Cell Physiol. 2010, 298(3):C542-9, PMCID: PMC2838571 link

8. ****Huang P, Li S, Shao M, Qi Q, Zhao F, You J, Mao T, Li W, Yan Z*, Liu Y*. Calorie restriction and exercise training share potent anti-inflammatory function in adipose tissues in ameliorating diet-induced obesity and insulin resistance in mice, Nutr Metab (Lond). 2010, 7(1):59. [Epub ahead of print] (*Corresponding authors) link

9. Zechner C, Lai L, Zechner JF, Geng T, Yan Z, Rumsey JW, Collia D, Chen Z, Wozniak DF, Leone TC, Kelly DP. Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity. Cell Metab. 2010 Dec 1;12(6):633-42. PubMed PMID: 21109195; PubMed Central PMCID: PMC2999961.

10.**** Geng T, Li P, Yin X, Yan Z. PGC-1α Promotes Nitric Oxide Antioxidant Defenses and Inhibits FOXO Signaling Against Cardiac Cachexia in Mice. Am J Pathol. 2011 Apr;178(4):1738-48. PubMed PMID: 21435455. Link

11. Wada S, Kato Y, Okutsu M, Miyaki S, Suzuki K, Yan Z, Schiaffino S, Asahara H, Ushida T, Akimoto T. Translational suppression of atrophic regulators by miR-23a integrates resistance to skeletal muscle atrophy. J Biol Chem. 2011 Sep 18. [Epub ahead of print] PubMed PMID: 21926429. Link

12. Griffin TM, Huebner J, Kraus VB, Yan Z, Guilak F. Effects of Voluntary Running on Osteoarthritis Progression and Inflammation in High-Fat Diet-induced Obese Mice. Arthritis Rheum. 2011 Sep 27. doi: 10.1002/art.33332. [Epub ahead of print] PubMed PMID: 21953366. Link

13. Meher AK, Sharma PR, Lira VA, Yamamoto M, Kensler TW, Yan Z, Leitinger N. Nrf2 deficiency in myeloid cells is not sufficient to protect mice from high-fat diet-induced adipose tissue inflammation and insulin resistance. Free Radic Biol Med. 2012 Feb 24;52(9):1708-1715. Link

14. Zhou B, Yang L, Li S, Huang J, Chen H, Hou L, Wang J, Green CD, Yan Z, Huang X, Kaeberlein M, Zhu L, Xiao H, Liu Y, Han JD. Midlife gene expressions identify modulators of aging through dietary interventions. Proc Natl Acad Sci U S A. 2012 May 8;109(19):E1201-9. Link

15. Zhang C, Li S, Yang L, Huang P, Li W, Wang S, Zhao G, Zhang M, Pang X, Yan Z, Liu Y, Zhao L. Structural modulation of gut microbiota in life-long calorie-restricted mice. Nat Commun. 2013;4:2163. PubMed PMID: 23860099; PubMed Central PMCID: PMC3717500. Link

16. Meng ZX, Li S, Wang L, Ko HJ, Lee Y, Jung DY, Okutsu M, Yan Z, Kim JK, Lin JD. Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation. Nat Med. 2013 May;19(5):640-5. Link

17. ****Zhang C, He Y, Okutsu M, Ong LC, Jin Y, Zheng L, Chow P, Yu S, Zhang M, Yan Z. Autophagy is involved in adipogenic differentiation by repressesing proteasome-dependent PPARγ2 degradation. Am J Physiol Endocrinol Metab. 2013 Aug 15;305(4):E530-9. PubMed PMID: 23800883.

18. Hindi SM, Mishra V, Bhatnagar S, Tajrishi MM, Ogura Y, Yan Z, Burkly LC, Zheng TS, Kumar A. Regulatory circuitry of TWEAK-Fn14 system and PGC-1α in skeletal muscle atrophy program. FASEB J. 2013 Dec 10. [Epub ahead of print] PubMed PMID: 24327607.

19. ****Okutsu M, Call JA, Lira VA, Zhang M, Donet JA, French BA, Martin KS, Peirce-Cottler SM, Rembold CM, Annex BH, Yan Z. Extracellular Superoxide Dismutase Ameliorates Skeletal Muscle Abnormalities, Cachexia and Exercise Intolerance in Mice with Congestive Heart Failure. Circ Heart Fail. 2014 Feb 12. [Epub ahead of print] PubMed PMID: 24523418 ."Current Editor's Picks"

20.
Taddeo EP, Laker RC, Breen DS, Akhtar YN, Kenwood BM, Liao JA, Zhang M, Fazakerley DJ, Tomsig JL, Harris TE, Keller SR, Chow JD, Lynch KR, Chokki M, Molkentin JD, Turner N, James DE, Yan Z*, Hoehn KL*. Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle. Mol Metab. 2014 Apr;3(2):124-34. doi: 10.1016/j.molmet.2013.11.003. PubMed PMID: 24634818.(*Corresponding authors)

21. Lee HY, Gattu AK, Camporez JP, Kanda S, Guigni B, Kahn M, Zhang D, Galbo T, Birkenfeld AL, Jornayvaz FR, Jurczak MJ, Choi CS, Yan Z, Williams RS, Shulman GI, Samuel VT. Muscle-specific activation of Ca2+/calmodulin-dependent protein kinase IV increases whole-body insulin action in mice. Diabetologia. 2014 Apr 11. [Epub ahead of print] PubMed PMID: 24718953.

22. ****Call JA, Chain KH, Martin KS, Lira VA, Okutsu M, Zhang M, Yan Z. Enhanced Skeletal Muscle Expression of EcSOD Mitigates Streptozotocin-Induced Diabetic Cardiomyopathy by Reducing Oxidative Stress and Aberrant Cell Signaling. Circ Heart Fail. 2014 PubMed PMID: 25504759.