Yan Li

University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

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Publications (12)54.19 Total impact

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    ABSTRACT: Skeletal muscle atrophy is debilitating outcome of a number of chronic diseases and conditions associated with loss of muscle innervation by motor neurons such as during aging and neurodegenerative diseases. We previously reported that denervation-induced loss of muscle mass is associated with activation of cytosolic phospholipase A2 (cPLA2), the rate limiting step for the release of arachidonic acid from membrane phospholipids, which then acts as a substrate for metabolic pathways that generate bioactive lipid mediators. In this study, we asked whether 5- and 12/15-lipoxygenase (LO) lipid metabolic pathways downstream of cPLA2, mediate denervation-induced muscle atrophy in mice. Both 5- and 12/15-LO were activated in response to surgical denervation, however, 12/15-LO activity was increased ~~ 2.5 fold versus~1.5 fold increase in activity of 5-LO. Genetic and pharmacological inhibition of 12/15-LO (but not 5-LO) significantly protected denervation-induced muscle atrophy, suggesting a selective role for 12/15-LO pathway in neurogenic muscle atrophy. The activation of 12/15-LO pathway (but not 5-LO) during muscle atrophy increased NADPH oxidase activity, protein ubiquitination and ubiquitin-proteasome mediated proteolytic degradation. In conclusion, this study reveals a novel pathway of neurogenic muscle atrophy and suggests that 12/15-LO may be a potential therapeutic target in diseases associated with loss of innervation and muscle atrophy.
    Free Radical Biology and Medicine 10/2013; 67. DOI:10.1016/j.freeradbiomed.2013.10.002 · 5.74 Impact Factor
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    ABSTRACT: Excess nutrient uptake leads to obesity, insulin resistance, and type 2 diabetes. Mammalian target of the rapamycin (mTOR), a major component of the nutrient-sensing pathway also regulates mitochondrial oxidative function. Rapamycin, a pharmacological inhibitor of mTOR, causes glucose intolerance and inhibits mitochondrial oxidative function. While a number of studies have focused on the effect of rapamycin on control wild-type mice, ours is the first to study the effect of rapamycin on mitochondrial gene expression and insulin sensitivity in the db/db mouse, a model of diabetic dyslipidemia. Female db/+ and db/db mice were fed ad libitum a rapamycin-containing diet or a control diet for 6 months, starting at two months of age. Body weight, fat mass, lean mass and food intake were measured monthly. Effect of rapamycin or control diet on markers of adipogenesis, fatty acid oxidation and mitochondrial biogenesis in the gonadal white adipose tissue (WAT) as well as different serum parameters were assessed. Whole body insulin sensitivity was measured by insulin tolerance test. Rapamycin feeding to db/db mice decreased body weight (58%) and fat mass (33%), elevated markers of fatty acid oxidation and mitochondrial biogenesis in WAT, reduced circulating non-esterified free fatty acids (NEFA), elevated circulating adiponectin and improved insulin sensitivity, compared to control diet fed db/db mice. These data demonstrate that rapamycin exhibits an anti-obesity effect and improves whole body insulin sensitivity in db/db mice and suggest an unexpected effect of simultaneous inhibition mTOR and leptin signaling in mice.
    06/2013; 1(2):114-123.

  • 19th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine; 11/2012
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    ABSTRACT: Age-related loss of muscle mass and function, sarcopenia, has a major impact on the quality of life in the elderly. Among the proposed causes of sarcopenia are mitochondrial dysfunction and accumulated oxidative damage during aging. Dietary restriction (DR), a robust dietary intervention that extends lifespan and modulates age-related pathology in a variety of species, has been shown to protect from sarcopenia in rodents. Although the mechanism(s) by which DR modulates aging are still not defined, one potential mechanism is through modulation of oxidative stress and mitochondrial dysfunction. To directly test the protective effect of DR against oxidative stress-induced muscle atrophy in vivo, we subjected mice lacking a key antioxidant enzyme, CuZnSOD (Sod1) to DR (60% of ad libitum fed diet). We have previously shown that the Sod1(-/-) mice exhibit an acceleration of sarcopenia associated with high oxidative stress, mitochondrial dysfunction, and severe neuromuscular innervation defects. Despite the dramatic atrophy phenotype in the Sod1(-/-) mice, DR led to a reversal or attenuation of reduced muscle function, loss of innervation, and muscle atrophy in these mice. DR improves mitochondrial function as evidenced by enhanced Ca(2+) regulation and reduction of mitochondrial reactive oxygen species (ROS). Furthermore, we show upregulation of SIRT3 and MnSOD in DR animals, consistent with reduced mitochondrial oxidative stress and reduced oxidative damage in muscle tissue measured as F(2) -isoprostanes. Collectively, our results demonstrate that DR is a powerful mediator of mitochondrial function, mitochondrial ROS production, and oxidative damage, providing a solid protection against oxidative stress-induced neuromuscular defects and muscle atrophy in vivo even under conditions of high oxidative stress.
    Aging cell 06/2012; 11(5):770-782. DOI:10.1111/j.1474-9726.2012.00843.x · 6.34 Impact Factor
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    ABSTRACT: Aging is associated with reduced ability to maintain normal glucose homeostasis. It has been suggested that an age-associated increase in chronic pro-inflammatory state could drive this reduction in glucoregulatory function. Thioredoxins (Trx) are oxido-reductase enzymes that play an important role in the regulation of oxidative stress and inflammation. In this study, we tested whether overexpression of Trx1 in mice [Tg(TRX1)+/0] could protect from glucose metabolism dysfunction caused by high fat diet feeding. Body weight and fat mass gains with high fat feeding were similar in Tg(TRX1)+/0 and wild-type mice; however, high fat diet induced glucose intolerance was reduced in Tg(TRX1)+/0mice relative to wild-type mice. In addition, expression of the pro-inflammatory cytokine TNF-α was reduced in adipose tissue of Tg(TRX1)+/0 mice compared to wild-type mice. These findings suggest that activation of thioredoxins may be a potential therapeutic target for maintenance of glucose metabolism with obesity or aging.
    05/2012; 2:17101. DOI:10.3402/pba.v2i0.17101
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. We sought to determine whether peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) would have a beneficial effect on this disease. PGC-1α transgenic mice were crossed with SOD1 mutant G93A DL mice. We observed a moderate but non-significant increase in average lifespan in PGC-1α/G93A DL mice, as compared with G93A DL mice (292 ± 3 days vs. 274 ± 7 days). Although the onset of ALS was not altered, progression of the disease was significantly slower (≈34% increase in duration) in the PGC-1α/G93A DL mice. These mice also exhibited markedly improved performance on the rotarod test, and the improved motor activity was associated with a decreased loss of motor neurons and less degeneration of neuromuscular junctions. A sustained level of excitatory amino acid transporter protein 2 (EAAT2) in astrocytes of the PGC-1α/G93A DL mice may contribute to neuronal protection.
    Muscle & Nerve 12/2011; 44(6):947-56. DOI:10.1002/mus.22217 · 2.28 Impact Factor

  • Free Radical Biology and Medicine 11/2011; 51. DOI:10.1016/j.freeradbiomed.2011.10.420 · 5.74 Impact Factor

  • Free Radical Biology and Medicine 11/2011; 51. DOI:10.1016/j.freeradbiomed.2011.10.431 · 5.74 Impact Factor

  • Free Radical Biology and Medicine 12/2010; 49. DOI:10.1016/j.freeradbiomed.2010.10.189 · 5.74 Impact Factor
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    ABSTRACT: Manganese superoxide dismutase (MnSOD) in the mitochondria plays an important role in cellular defense against oxidative damage. Homozygous MnSOD knockout (Sod2(-/-)) mice are neonatal lethal, indicating the essential role of MnSOD in early development. To investigate the potential cellular abnormalities underlying the aborted development of Sod2(-/-) mice, we examined the growth of isolated mouse embryonic fibroblasts (MEFs) from Sod2(-/-) mice. We found that the proliferation of Sod2(-/-) MEFs was significantly decreased compared with wild-type MEFs despite the absence of morphological differences. The Sod2(-/-) MEFs produced less cellular ATP, had lower O(2) consumption, generated more superoxide, and expressed less Prdx3 protein. Furthermore, the loss of MnSOD dramatically altered several markers involved in cell proliferation and growth, including decreased growth stimulatory function of mTOR signaling and enhanced growth inhibitory function of GSK-3β signaling. Interestingly, the G-protein-coupled receptor-mediated intracellular Ca(2+) signal transduction was also severely suppressed in Sod2(-/-) MEFs. Finally, the ratio of microtubule-associated protein light chain 3 (LC3)-II/LC3-I, an index of autophagic activity, was increased in Sod2(-/-) MEFs, consistent with a reduction in mTOR signal transduction. These data demonstrate that MnSOD deficiency results in alterations in several key signaling pathways, which may contribute to the lethal phenotype of Sod2(-/-) mice.
    Free Radical Biology and Medicine 11/2010; 49(8):1255-62. DOI:10.1016/j.freeradbiomed.2010.07.006 · 5.74 Impact Factor
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    ABSTRACT: To test the impact of increased mitochondrial oxidative stress as a mechanism underlying aging and age-related pathologies, we generated mice with a combined deficiency in two mitochondrial-localized antioxidant enzymes, Mn superoxide dismutase (MnSOD) and glutathione peroxidase-1 (Gpx-1). We compared life span, pathology, and oxidative damage in Gpx1(-/-), Sod2(+/-)Gpx1(+/-), Sod2(+/-)Gpx1(-/-), and wild-type control mice. Oxidative damage was elevated in Sod2(+/-)Gpx1(-/-) mice, as shown by increased DNA oxidation in liver and skeletal muscle and increased protein oxidation in brain. Surprisingly, Sod2(+/-)Gpx1(-/-) mice showed no reduction in life span, despite increased levels of oxidative damage. Consistent with the important role for oxidative stress in tumorigenesis during aging, the incidence of neoplasms was significantly increased in the older Sod2(+/-)Gpx1(-/-) mice (28-30 months). Thus, these data do not support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice and do not support the oxidative stress theory of aging.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 09/2009; 64(12):1212-20. DOI:10.1093/gerona/glp132 · 5.42 Impact Factor
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    ABSTRACT: The mitochondrial form of thioredoxin, thioredoxin 2 (Txn2), plays an important role in redox control and protection against ROS-induced mitochondrial damage. To evaluate the effect of reduced levels of Txn2 in vivo, we measured oxidative damage and mitochondrial function using mice heterozygous for the Txn2 gene (Txn2(+/-)). The Txn2(+/-) mice showed approximately 50% decrease in Trx-2 protein expression in all tissues without upregulating the other major components of the antioxidant defense system. Reduced levels of Txn2 resulted in decreased mitochondrial function as shown by reduced ATP production by isolated mitochondria and reduced activity of electron transport chain complexes (ETCs). Mitochondria isolated from Txn2(+/-) mice also showed increased ROS production compared to wild type mice. The Txn2(+/-) mice showed increased oxidative damage to nuclear DNA, lipids, and proteins in liver. In addition, we observed an increase in apoptosis in liver from Txn2(+/-) mice compared with wild type mice after diquat treatment. Our results suggest that Txn2 plays an important role in protecting the mitochondria against oxidative stress and in sensitizing the cells to ROS-induced apoptosis.
    Free Radical Biology and Medicine 04/2008; 44(5):882-92. DOI:10.1016/j.freeradbiomed.2007.11.018 · 5.74 Impact Factor

Publication Stats

232 Citations
54.19 Total Impact Points


  • 2008-2013
    • University of Texas Health Science Center at San Antonio
      • • Barshop Institute for Longevity and Aging Studies
      • • Department of Cellular and Structural Biology
      • • Department of Epidemiology and Biostatistics
      San Antonio, Texas, United States
  • 2009
    • University of Texas at San Antonio
      San Antonio, Texas, United States