- PhD, University of Texas Health Sciences Center, Houston
- Associate Professor, Medicine- Cardiovascular Medicine
- Phone: 434-982-4477
- Email: email@example.com
Molecular and signaling mechanisms of skeletal muscle plasticity.
Skeletal muscle is remarkably plastic such that alteration in contractile load, hormonal shifts, or systemic diseases can induce profound phenotypic changes. Research in this laboratory focuses on skeletal muscle adaptations induced by endurance exercise and maladaptation under chronic heart failure and type 2 diabetes mellitus conditions. We employ the state-of-the-art technologies, such as in vivo bioluminescence imaging, in a variety of experimental models ranging from cultured cells to genetically engineered mice. Our goal is to improve the understanding of the molecular and signaling mechanisms underlying physiological adaptation and pathological maladaptation in skeletal muscle.
1. Exercise-induced skeletal muscle adaptation
Accumulating evidence suggests that increased peroxisome proliferator-activated receptor γ co-activator-1a (Pgc-1a) expression plays a pivotal role in exercise-induced adaptation in skeletal muscle; however, the molecular mechanisms remain elusive. Our studies defined an essential role of p38γ mitogen-activated protein kinase (MAPK) in promoting Pgc-1a transcription and metabolic adaptation (mitochondrial biogenesis and angiogenesis). We have also confirmed that p38a and p38β and their downstream E3 ubiquitin ligases and autophagy-related genes in the proteolytic processes in muscle wasting. We are currently investigating the isoform-specific function of p38 MAPK in physiological adaptation induced by endurance exercise training and in pathological maladaptations in catabolic wasting and metabolic disorders. 2. Mitophagy in type 2 diabetes mellitus
Impaired mitochondria play a critical role in the pathogenesis of type 2 diabetes mellitus; however, the precise mechanism remains poorly understood. We have obtained substantial evidence that lipid overload induces accumulation of damaged mitochondria in skeletal muscle. We are taking advantage of various experimental models ranging from cultured muscle cells to genetically engineered mice to address the importance of mitochondrial maintenance in insulin resistance. Specifically, we are interested in the critical steps involved in mitochondrial degeneration and clearance (mitochondrial autophagy or mitophagy).
3. NO-dependent protection against muscle wasting
Cachexia is a severe medical condition characterized by loss of muscle mass (catabolic wasting) and is associated with many chronic diseases. The direct causes are skeletal muscle abnormalities as consequences of accumulation of reactive oxygen species (ROS) and associated cellular damages. It is well known that muscles of oxidative phenotype are resistant to catabolic wasting; however, the underlying mechanism remains to be defined. We have shown that in a mouse genetic model of CHF [cardiac-specific calsequestrin (CSQ) transgenic mice] this muscle protection is due to a nitric oxide (NO)-dependent antioxidant defense through activation of the Keap1/Nrf2 scaffold protein-transcription factor complex. We are focusing on the regulation and function of extracellular superoxide dismutase (EcSOD or SOD3) in NO-dependent protection against cachexia in skeletal muscle using both transgenic and somatic gene transfer approaches.
- Call J, Chain K, Martin K, Lira V, Okutsu M, Zhang M, Yan Z. Enhanced skeletal muscle expression of extracellular superoxide dismutase mitigates streptozotocin-induced diabetic cardiomyopathy by reducing oxidative stress and aberrant cell signaling. Circulation. Heart failure. 2014;8(1): 188-97. PMID: 25504759 | PMCID: PMC4445759
- Kenwood B, Weaver J, Bajwa A, Poon I, Byrne F, Murrow B, Calderone J, Huang L, Divakaruni A, Tomsig J, Okabe K, Lo R, Cameron Coleman G, Columbus L, Yan Z, Saucerman J, Smith J, Holmes J, Lynch K, Ravichandran K, Uchiyama S, Santos W, Rogers G, Okusa M, Bayliss D, Hoehn K. Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane. Molecular metabolism. 2014;3(2): 114-23. PMID: 24634817 | PMCID: PMC3953706
- Laker R, Connelly J, Yan Z. Response to comment on Laker et al. Exercise prevents maternal high-fat diet-induced hypermethylation of the pgc-1α gene and age-dependent metabolic dysfunction in the offspring. Diabetes 2014;63:1605-1611. Diabetes. 2014;63(5): e6-7. PMID: 24757208
- Laker R, Lillard T, Okutsu M, Zhang M, Hoehn K, Connelly J, Yan Z. Exercise prevents maternal high-fat diet-induced hypermethylation of the Pgc-1α gene and age-dependent metabolic dysfunction in the offspring. Diabetes. 2014;63(5): 1605-11. PMID: 24430439
- Okutsu M, Call J, Lira V, Zhang M, Donet J, French B, Martin K, Peirce-Cottler S, Rembold C, Annex B, Yan Z. Extracellular superoxide dismutase ameliorates skeletal muscle abnormalities, cachexia, and exercise intolerance in mice with congestive heart failure. Circulation. Heart failure. 2014;7(3): 519-30. PMID: 24523418 | PMCID: PMC4080303
- Taddeo E, Laker R, Breen D, Akhtar Y, Kenwood B, Liao J, Zhang M, Fazakerley D, Tomsig J, Harris T, Keller S, Chow J, Lynch K, Chokki M, Molkentin J, Turner N, James D, Yan Z, Hoehn K. Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle. Molecular metabolism. 2014;3(2): 124-34. PMID: 24634818 | PMCID: PMC3953683
- Hochreiter-Hufford A, Lee C, Kinchen J, Sokolowski J, Arandjelovic S, Call J, Klibanov A, Yan Z, Mandell J, Ravichandran K. Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion. Nature. 2013;497(7448): 263-7. PMID: 23615608 | PMCID: PMC3773542
- Katwal A, Konkalmatt P, Piras B, Hazarika S, Li S, John Lye R, Sanders J, Ferrante E, Yan Z, Annex B, French B. Adeno-associated virus serotype 9 efficiently targets ischemic skeletal muscle following systemic delivery. Gene therapy. 2013;20(9): 930-8. PMID: 23535898 | PMCID: PMC3758463
- Lira V, Okutsu M, Zhang M, Greene N, Laker R, Breen D, Hoehn K, Yan Z. Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2013;27(10): 4184-93. PMID: 23825228 | PMCID: PMC4046188
- Zhang C, He Y, Okutsu M, Ong L, Jin Y, Zheng L, Chow P, Yu S, Zhang M, Yan Z. Autophagy is involved in adipogenic differentiation by repressesing proteasome-dependent PPARγ2 degradation. American journal of physiology. Endocrinology and metabolism. 2013;305(4): E530-9. PMID: 23800883
- Dey B, Gagan J, Yan Z, Dutta A. miR-26a is required for skeletal muscle differentiation and regeneration in mice. Genes & development. 2012;26(19): 2180-91. PMID: 23028144 | PMCID: PMC3465739
- Gagan J, Dey B, Layer R, Yan Z, Dutta A. Notch3 and Mef2c Are Mutually Antagonistic via Mkp1 and miR-1/206 in Differentiating Myoblasts. The Journal of biological chemistry. 2012. PMID: 23055528 | PMCID: PMC3504751
- Meher A, Sharma P, Lira V, Yamamoto M, Kensler T, 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 radical biology & medicine. 2012;52(9): 1708-15. PMID: 22370093 | PMCID: PMC3383807
- Yan Z, Lira V, Greene N. Exercise training-induced regulation of mitochondrial quality. Exercise and sport sciences reviews. 2012;40(3): 159-64. PMID: 22732425 | PMCID: PMC3384482
- Gagan J, Dey B, Layer R, Yan Z, Dutta A. MicroRNA-378 targets the myogenic repressor MyoR during myoblast differentiation. The Journal of biological chemistry. 2011;286(22): 19431-8. PMID: 21471220 | PMCID: PMC3103322
- Geng T, Li P, Yin X, Yan Z. PGC-1α promotes nitric oxide antioxidant defenses and inhibits FOXO signaling against cardiac cachexia in mice. The American journal of pathology. 2011;178(4): 1738-48. PMID: 21435455 | PMCID: PMC3078433
- Huang P, Li S, Shao M, Qi Q, Zhao F, You J, Mao T, Li W, Yan Z, Liu Y. Calorie restriction and endurance exercise share potent anti-inflammatory function in adipose tissues in ameliorating diet-induced obesity and insulin resistance in mice. Nutrition & metabolism. 2010;7 59. PMID: 20633301 | PMCID: PMC2914080
- Lira V, Benton C, Yan Z, Bonen A. PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity. American journal of physiology. Endocrinology and metabolism. 2010;299(2): E145-61. PMID: 20371735 | PMCID: PMC2928513
- Yan Z, Okutsu M, Akhtar Y, Lira V. Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle. Journal of applied physiology (Bethesda, Md. : 1985). 2010;110(1): 264-74. PMID: 21030673 | PMCID: PMC3253006
- Exercise, PGC-1alpha, and metabolic adaptation in skeletal muscle. Applied physiology, nutrition, and metabolism = Physiologie appliquée, nutrition et métabolisme. 2009;34(3): 424-7. PMID: 19448709 | PMCID: PMC3354917