Liping Zhang

• Baylor College of Medicine

Background: CKD induces loss of muscle proteins partly by suppressing muscle protein synthesis. Muscles of mice with CKD have increased expression of nucleolar protein 66 (NO66), as do muscle biopsy specimens from patients with CKD or those undergoing hemodialysis. Inflammation stimulates NO66 expression and changes in NF-κB mediate the response....

Loss of muscle proteins increases the morbidity and mortality of patients with chronic kidney disease (CKD) and there are no reliable preventive treatments. We uncovered a STAT3, CEBPδ to myostatin signaling pathway that activates muscle protein degradation in mice with CKD or cancer; we also identified a small molecule inhibitor of STAT3 (TTI-101)...

Chronic kidney disease (CKD) causes loss of lean body mass by multiple mechanisms. This study examines whether autophagy-mediated proteolysis contributes to CKD-induced muscle wasting. We tested autophagy in the muscle of CKD mice with plantaris muscle overloading to mimic resistance exercise or with acupuncture plus low frequency electrical stimul...

Objective To investigate the effect of vascular endothelial growth factor (VEGF) overexpression on the phenotype, proliferation and multilineage differentiation ability of human adipose-derived stem cells (hADSCs). Methods Passage-2 hADSCs were transfected with pIRES2-EGFP-VEGF plasmid using DOTAP liposomal technique, whereas hADSCs in control grou...

Fibrosis in skeletal muscle develops after injury or in response to chronic kidney disease (CKD), but the origin of cells becoming fibrous tissue and the initiating and sustaining mechanisms causing muscle fibrosis are unclear. We identified muscle fibro/adipogenic progenitor cells (FAPs) that potentially differentiate into adipose tissues or fibro...

Insulin resistance refers to reduced sensitivity of organs to insulin-initiated biologic processes that result in metabolic defects. Insulin resistance is common in patients with end-stage renal disease but also occurs in patients with chronic kidney disease (CKD), even when the serum creatinine is minimally increased. Following insulin binding to...

Background/objective: In mice, a high-fat diet (HFD) induces obesity, insulin resistance and myostatin production. We tested whether inhibition of myostatin in mice can reverse these HFD-induced abnormalities. Subjects/methods: C57BL/6 mice were fed a HFD for 16 weeks including the final 4 weeks some mice were treated with an anti-myostatin pept...

Cachexia occurs in patients with advanced cancers. Despite the adverse clinical impact of cancer-induced muscle wasting, pathways causing cachexia are controversial and clinically reliable therapies are not available. A trigger of muscle protein loss is the JAK/Stat pathway and indeed, we found that conditioned media from C26 colon carcinoma (C26)...

An increase in intramuscular adipocyte tissue (IMAT) is associated with glucose dysregulation, decreased muscle strength, and increased risk of disability. Unfortunately, the mechanisms stimulating intramuscular adipogenesis remain unclear. We found that dexamethasone (Dex) administration to mice with injured muscles stimulates the accumulation of...

The mechanisms underlying the development of aging-induced muscle atrophy are unclear. By microRNA array and individual qPCR analyses, we found significant up-regulation of miR-29 in muscles of aged rodents vs. results in young. With aging, p85α, IGF-1 and B-myb muscle levels were lower while the expression of certain cell arrest proteins (p53, p16...

Catabolic conditions like chronic kidney disease (CKD) cause loss of muscle mass by unclear mechanisms. In muscle biopsies from CKD patients, we found activated Stat3 (p-Stat3) and hypothesized that p-Stat3 initiates muscle wasting. We created mice with muscle-specific knockout (KO) that prevents activation of Stat3. In these mice, losses of body a...

In catabolic conditions such as aging and diabetes, IGF signaling is impaired and fibrosis develops in skeletal muscles. To examine if impaired IGF signaling initiates muscle fibrosis, we generated IGF-1R(+/-) heterozygous mice by crossing LoxP floxed IGF-1R (exon 3) mice with MyoD-cre mice. IGF-1R(+/-) mice were studied because we were unable to o...

Cachexia is a devastating complication of cancer. The mechanisms by which cancers cause cachexia are unclear and there are few successful therapeutic options. In muscles from mouse models of cancer cachexia, we found increased STAT3 phosphorylation associated with muscle atrophy. In muscle cells (C2C12 myotubes) incubated with media from cultured L...

Glucocorticoids are elevated in many pathological conditions and are associated with muscle loss, but the mechanisms are not fully understood. Defects in satellite cell function contribute to the development of muscle atrophy. Here, we demonstrated a new mechanism of dexamethasone‐induced muscle atrophy by suppression of satellite cell function. De...

Myostatin inhibits skeletal muscle growth. Animals lacking myostatin develops significantly larger muscles, which are associated with reduced adiposity and lower blood glucose. We investigated whether myostatin inhibition would improve the metabolic profile of diabetic mice. C56/BL6 mice were fed a high fat diet (HFD) for 10 months. During the last...

Insulin resistance from chronic kidney disease (CKD) stimulates muscle protein wasting but mechanisms causing this resistance are controversial. To help resolve this, we used microarray analyses to identify initiators of insulin resistance in the muscles of mice with CKD, glucose intolerance, and insulin resistance. CKD raised mRNAs of inflammatory...

C2C12 myotubes were serum starved, and then treated with a mixture of IL-6 (2 ng/ml), TNF-α (2 ng/ml), and IFN-γ (2 ng/ml) for 24 hours and compared with control (CTL) myotubes without cytokine exposure. Representative immunoblots of SIRP-α and GAPDH (left panel) with quantitative band density relative to GAPDH is shown (right panel; *, p<0.05 vs....

Supplemental Table 2. RT-PCR Primers.

Fold change of mRNA of CKD mice compared to control mice was evaluated by microarray analysis and confirmatory RT-PCR. (n=3).

Glucocorticoids production is increased in many pathological conditions that are associated with muscle loss, but their role in causing muscle wasting is not fully understood. We have demonstrated a new mechanism of glucocorticoid-induced muscle atrophy: Dexamethasone (Dex) suppresses satellite cell function contributing to the development of muscl...

Myostatin inhibition prevents Dex induced body and muscle weight loss. Mice were treated with Dex plus PBS or Dex plus anti-myostatin peptibody for 14 days. A. Body weight changes (*p<0.05 vs. CTRL mice; n = 8 mice). B. Gastrocnemius muscle weight (*p<0.05 vs. CTRL mice; n = 8 mice). C. Myofiber distribution. D. Representative western blots of Atro...

Dex inhibits expression of inflammatory genes in injured muscle. Mice were treated with Dex for 14 days and TA muscles were injured at different times. mRNA expression of inflammatory genes was evaluated by RT-PCR. Primer sequences will be sent upon request. (TIF)

Our recent studies have shown that bone marrow-derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. However, the molecular mechanisms underlying the recruitment and activation of bone marrow-derived fibroblast precursors are incompletely understood. We found that interleukin 6 was induced in the kidney in a...

Following injury, skeletal muscle achieves repair by a highly coordinated, dynamic process resulting from interplay among numerous inflammatory, growth factors and myogenic regulators. To identify genes involved in muscle regeneration, we used a microarray analysis; there was a significant increase in the expression of a group of integrin genes. To...

The mechanisms underlying the muscle wasting that accompanies CKD are not well understood. Animal models suggest that impaired differentiation of muscle progenitor cells may contribute. Expression of the myogenesis-suppressing transcription factor Ying Yang-1 increases in muscle of animals with CKD, but the mechanism underlying this increased expre...

Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we...

Mechanical stress plays an important role in proliferation of venous smooth muscle cells (SMCs) in neointima, a process of formation that contributes to failure of vein grafts. However, it is unknown what intracellular growth signal leads to proliferation of venous SMCs. The objective of this study is to identify mechanisms of mechanical stretch on...

With muscle wasting, caspase-3 activation and the ubiquitin-proteasome system act synergistically to increase the degradation of muscle proteins. Whether proteasome activity is also elevated in response to catabolic conditions is unknown. We find that caspase-3 increases proteasome activity in myotubes but not in myoblasts. This difference is relat...

X-chromosome-linked inhibitor of apoptosis protein (XIAP) is an endogenous caspase inhibitor. Caspase-3 contributes to the muscle wasting associated with chronic kidney disease (CKD) and other systemic illnesses, but whether XIAP modulates muscle wasting in CKD is unknown. Here, overexpression of XIAP in cultured skeletal muscle cells decreased pro...

Muscle wasting in chronic kidney disease (CKD) begins with impaired insulin/IGF-1 signaling, causing abnormal protein metabolism. In certain models of muscle atrophy, reduced satellite cell function contributes to atrophy, but how CKD affects satellite cell function is unknown. Here, we found that isolated satellite cells from mice with CKD had les...

Only a few specific chemokines that mediate interactions between inflammatory and satellite cells in muscle regeneration have been identified. The chemokine CXCL16 differs from other chemokines because it has both a transmembrane region and active, soluble chemokine forms. Indeed, we found increased expression of CXCL16 and its receptor, CXCR6, in...

Animal studies suggest that increased levels of circulating angiotensin II (AngII) could contribute to the loss of lean body mass in chronic kidney disease, but the mechanism by which this occurs is unclear. Here, AngII infusion increased circulating IL-6 and its hepatic production in wild-type mice, suggesting that AngII-induced inflammation may t...

We have identified an accession (LA2093) within the tomato wild species Solanum pimpinellifolium with many desirable characteristics, including biotic and abiotic stress tolerance and good fruit quality. To utilize the full genetic potential of LA2093 in tomato breeding, we have developed a linkage map based on an F(2) population of a cross between...

To determine the mechanisms involved in regulating the balance between apoptosis and survival in vascular smooth muscle cells (VSMC), we studied anti-apoptotic stimuli that can counteract pro-apoptotic events in the process of early atherosclerotic lesions formation. Such a process involves VSMC accumulation even in the presence of oxidized low den...

Conditions accelerating muscle proteolysis are frequently associated with defective phosphatidylinositol 3-kinase (PI3K)/Akt signaling and reduced PI3K-generated phosphatidylinositol 3,4,5-triphosphate (PIP(3)). We evaluated the control of muscle protein synthesis and degradation in mouse models of type 1 and 2 diabetes to determine whether defects...

The purpose of this study was to determine whether the rates of tomato seed germination under different stress and nonstress conditions were under common genetic controls by examining quantitative trait loci (QTL) affecting such traits. Seeds of BC(1) progeny of a cross between a slow-germinating tomato breeding line and a rapid-germinating tomato...

Muscle atrophy in catabolic illnesses is due largely to accelerated protein degradation. Unfortunately, methods for detecting accelerated muscle proteolysis are cumbersome. The goal of this study was to develop a method for detecting muscle protein breakdown and assess the effectiveness of anticatabolic therapy. In rodent models of catabolic condit...

Increased expression of the IGF-I receptor (IGF-IR) is associated with proliferation and survival of vascular smooth muscle cells (VSMCs). In cultured VSMCs, we reported that angiotensin II (Ang II) increases transcription and expression of IGF-IR. Now, we show that mesenteric arteries of rats infused with Ang II develop thickening and increased IG...

Activation of nuclear factor (NF)-kappaB by angiotensin II (Ang II) plays an essential role in stimulating expression of vascular adhesion molecules, which are essential for vascular inflammation. We report that Ang II activates NF-kappaB by phosphorylating its p65 subunit via a pathway mediated partially by ribosomal S6 kinase (RSK). In investigat...

Angiotensin II (Ang II) promotes vascular inflammation and remodeling via activation of nuclear factor kappaB (NF-kappaB)-mediated transcription of proinflammatory genes such as interleukin-6 (IL-6). We examined the signaling mechanism whereby Ang II activates NF-kappaB in vascular smooth muscle cells (VSMCs). Ang II treatment did not increase phos...

Serum and glucocorticoid inducible protein kinase (SGK) plays a crucial role in promoting cell survival, but the mechanisms for this response are not clear. We show that SGK is involved in the regulation of apoptosis in breast cancer cells by modulating the transcriptional activity of nuclear transcription factor kappaB (NF-kappaB). High levels of...

Prostate cancer is a major health threat for American men. Therefore, the development of effective therapeutic options is an urgent issue for prostate cancer treatment. In this study, we evaluated the effect of glycogen synthase kinase-3beta (GSK-3beta) suppression on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis...

The purpose of this study was to determine the genetic relationship between salt tolerance (ST) during seed germination (SG) and vegetative stage (VS) in tomato by comparing quantitative trait loci (QTLs) which contribute to ST at these two developmental stages. A total of 145 F9 recombinant inbred lines (RILs) of a cross between a salt-sensitive L...

The purpose of this study was to examine the genetic relationships among cold, salt and drought tolerance during seed germination in tomato by the analysis of response and correlated response to selection and by the identification and comparison of QTLs affecting these traits. Seeds of BC1 progeny of an interspecific cross between a slow-germinatin...

A BC1 population (N = 1000) of an F1 hybrid between a stress-sensitive Lycopersicon esculentum breeding line (NC84173; maternal and recurrent parent) and a germination stress-tolerant Lycopersicon pimpinellifolium accession (LA722) was evaluated for seed germination rate under drought stress (DS) (14% w/v polyethyleneglycol-8000, water potential ap...

The purpose of this research was to identify and characterize resistance gene analogs (RGAs) in tomato by PCR amplification of genomic DNA using primers designed based on the conserved amino-acid domains of several known plant disease resistance genes (R genes). Amplified DNAs from a Lycopersicon esculentum × L. hirsutum backcross (BC1) population...

Most commercial cultivars of tomato, Lycopersicon esculentum Mill., are susceptible to early blight (EB), a devastating fungal (Alternaria solani Sorauer) disease of tomato in the U.S. and elsewhere in the world. Currently, sanitation, long crop rotation, and routine application of fungicides are the most common disease control measures. Although n...

Most commercial cultivars of tomato, Lycopersicon esculentum Mill., are susceptible to early blight (EB), a devastating fungal ( Alternaria solani Sorauer) disease of tomato in the northern and eastern parts of the U.S. and elsewhere in the world. The disease causes plant defoliation, which reduces yield and fruit quality, and contributes to signif...

A molecular linkage map of tomato was constructed based on a BC1 population (N = 145) of a cross between Lycopersicon esculentum Mill. line NC84173 (maternal and recurrent parent) and Lycopersicon hirsutum Humb. and Bonpl. accession PI126445. NC84173 is an advanced breeding line that is resistant to several tomato diseases, not including early blig...

The purpose of this study was to identify quantitative trait loci (QTLs) for salt tolerance (ST) during vegetative growth (VG) in tomato by distributional extreme analysis and compare them with the QTLs previously identified for this trait. A BC1 population (N = 792) of a cross between a moderately salt-sensitive Lycopersicon esculentum Mill. breed...