6 results on '"Moylan, Jennifer S."'
Search Results
2. Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes.
- Author
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Gilliam LA, Moylan JS, Patterson EW, Smith JD, Wilson AS, Rabbani Z, and Reid MB
- Subjects
- Cell Differentiation drug effects, Cell Differentiation physiology, Cell Line, Humans, Metabolism drug effects, Metabolism physiology, Muscle Fibers, Skeletal cytology, Doxorubicin pharmacology, Mitochondria drug effects, Mitochondria metabolism, Muscle Fibers, Skeletal drug effects, Muscle Fibers, Skeletal metabolism, Reactive Oxygen Species metabolism
- Abstract
Doxorubicin, a commonly prescribed chemotherapeutic agent, causes skeletal muscle wasting in cancer patients undergoing treatment and increases mitochondrial reactive oxygen species (ROS) production. ROS stimulate protein degradation in muscle by activating proteolytic systems that include caspase-3 and the ubiquitin-proteasome pathway. We hypothesized that doxorubicin causes skeletal muscle catabolism through ROS, causing upregulation of E3 ubiquitin ligases and caspase-3. We tested this hypothesis by exposing differentiated C2C12 myotubes to doxorubicin (0.2 μM). Doxorubicin decreased myotube width 48 h following exposure, along with a 40-50% reduction in myosin and sarcomeric actin. Cytosolic oxidant activity was elevated in myotubes 2 h following doxorubicin exposure. This increase in oxidants was followed by an increase in the E3 ubiquitin ligase atrogin-1/muscle atrophy F-box (MAFbx) and caspase-3. Treating myotubes with SS31 (opposes mitochondrial ROS) inhibited expression of ROS-sensitive atrogin-1/MAFbx and protected against doxorubicin-stimulated catabolism. These findings suggest doxorubicin acts via mitochondrial ROS to stimulate myotube atrophy.
- Published
- 2012
- Full Text
- View/download PDF
3. TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm weakness.
- Author
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Gilliam LA, Moylan JS, Ferreira LF, and Reid MB
- Subjects
- Animals, Antineoplastic Agents adverse effects, Base Sequence, DNA Primers genetics, Etanercept, Immunoglobulin G pharmacology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle Weakness genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I deficiency, Receptors, Tumor Necrosis Factor, Type I genetics, Signal Transduction drug effects, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha genetics, Up-Regulation drug effects, Diaphragm drug effects, Diaphragm physiopathology, Doxorubicin adverse effects, Muscle Weakness chemically induced, Muscle Weakness physiopathology, Receptors, Tumor Necrosis Factor, Type I physiology, Tumor Necrosis Factor-alpha physiology
- Abstract
Doxorubicin, a common chemotherapeutic agent, causes respiratory muscle weakness in both patients and rodents. Tumor necrosis factor-α (TNF), a proinflammatory cytokine that depresses diaphragm force, is elevated following doxorubicin chemotherapy. TNF-induced diaphragm weakness is mediated through TNF type 1 receptor (TNFR1). These findings lead us to hypothesize that TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm muscle weakness. We tested this hypothesis by treating C57BL/6 mice with a clinical dose of doxorubicin (20 mg/kg) via intravenous injection. Three days later, we measured contractile properties of muscle fiber bundles isolated from the diaphragm. We tested the involvement of TNF/TNFR1 signaling using pharmaceutical and genetic interventions. Etanercept, a soluble TNF receptor, and TNFR1 deficiency protected against the depression in diaphragm-specific force caused by doxorubicin. Doxorubicin stimulated an increase in TNFR1 mRNA and protein (P < 0.05) in the diaphragm, along with colocalization of TNFR1 to the plasma membrane. These results suggest that doxorubicin increases diaphragm sensitivity to TNF by upregulating TNFR1, thereby causing respiratory muscle weakness.
- Published
- 2011
- Full Text
- View/download PDF
4. Doxorubicin causes diaphragm weakness in murine models of cancer chemotherapy.
- Author
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Gilliam LA, Moylan JS, Callahan LA, Sumandea MP, and Reid MB
- Subjects
- Animals, Diaphragm pathology, Diaphragm physiopathology, Injections, Intraperitoneal adverse effects, Injections, Intravenous adverse effects, Male, Mice, Mice, Inbred C57BL, Muscle Weakness pathology, Muscle Weakness physiopathology, Respiratory Paralysis pathology, Respiratory Paralysis physiopathology, Antibiotics, Antineoplastic toxicity, Diaphragm drug effects, Disease Models, Animal, Doxorubicin toxicity, Muscle Weakness chemically induced, Respiratory Paralysis chemically induced
- Abstract
Doxorubicin is a chemotherapeutic agent prescribed for a variety of tumors. While undergoing treatment, patients exhibit frequent symptoms that suggest respiratory muscle weakness. Cancer patients can receive doxorubicin chemotherapy through either intravenous (IV) or intraperitoneal (IP) injections. We hypothesized that respiratory muscle function would be depressed in a murine model of chemotherapy. We tested this hypothesis by treating C57BL/6 mice with a clinical dose of doxorubicin (20 mg/kg) via IV or IP injection. Three days later we measured contractile properties of muscle fiber bundles isolated from the diaphragm. Doxorubicin consistently depressed diaphragm force with both methods of administration (P < 0.01). Doxorubicin IP exaggerated the depression in diaphragm force and stimulated tissue inflammation and muscle fiber injury. These results suggest that clinically relevant doses of doxorubicin cause respiratory muscle weakness and that the loss of function depends, in part, on the route of administration., (Copyright © 2010 Wiley Periodicals, Inc.)
- Published
- 2011
- Full Text
- View/download PDF
5. Doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle.
- Author
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Gilliam LA, Ferreira LF, Bruton JD, Moylan JS, Westerblad H, St Clair DK, and Reid MB
- Subjects
- Analysis of Variance, Animals, Blotting, Western, Calcium metabolism, Enzyme-Linked Immunosorbent Assay, Male, Mice, Mice, Knockout, Muscle Fatigue drug effects, Muscle Weakness metabolism, Muscle, Skeletal metabolism, Muscle, Skeletal physiology, Muscle, Skeletal physiopathology, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Tumor Necrosis Factor, Type I genetics, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Doxorubicin administration & dosage, Muscle Contraction drug effects, Muscle Strength drug effects, Muscle, Skeletal drug effects, Receptors, Tumor Necrosis Factor, Type I metabolism
- Abstract
Cancer patients receiving doxorubicin chemotherapy experience both muscle weakness and fatigue. One postulated mediator of the muscle dysfunction is an increase in tumor necrosis factor-alpha (TNF), a proinflammatory cytokine that mediates limb muscle contractile dysfunction through the TNF receptor subtype 1 (TNFR1). Our main hypothesis was that systemic doxorubicin administration would cause muscle weakness and fatigue. Systemic doxorubicin administration (20 mg/kg) depressed maximal force of the extensor digitorum longus (EDL; P < 0.01), accelerated EDL fatigue (P < 0.01), and elevated serum TNF levels (P < 0.05) 72 h postinjection. Genetic TNFR1 deficiency prevented the fall in specific force caused by systemic doxorubicin, without protecting against fatigue (P < 0.01). These results demonstrate that clinical doxorubicin concentrations disrupt limb muscle function in a TNFR1-dependent manner.
- Published
- 2009
- Full Text
- View/download PDF
6. Doxorubicin causes diaphragm weakness in murine models of cancer chemotherapy
- Author
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Gilliam, Laura A. A., Moylan, Jennifer S., Callahan, Leigh Ann, Sumandea, Marius P., and Reid, Michael B.
- Subjects
Male ,Mice, Inbred C57BL ,Disease Models, Animal ,Mice ,Antibiotics, Antineoplastic ,Muscle Weakness ,Doxorubicin ,Diaphragm ,Injections, Intravenous ,Animals ,Respiratory Paralysis ,Article ,Injections, Intraperitoneal - Abstract
Doxorubicin is a chemotherapeutic agent prescribed for a variety of tumors. While undergoing treatment, patients exhibit frequent symptoms that suggest respiratory muscle weakness. Cancer patients can receive doxorubicin chemotherapy through either intravenous (IV) or intraperitoneal (IP) injections. We hypothesized that respiratory muscle function would be depressed in a murine model of chemotherapy. We tested this hypothesis by treating C57BL/6 mice with a clinical dose of doxorubicin (20 mg/kg) via IV or IP injection. Three days later we measured contractile properties of muscle fiber bundles isolated from the diaphragm. Doxorubicin consistently depressed diaphragm force with both methods of administration (P0.01). Doxorubicin IP exaggerated the depression in diaphragm force and stimulated tissue inflammation and muscle fiber injury. These results suggest that clinically relevant doses of doxorubicin cause respiratory muscle weakness and that the loss of function depends, in part, on the route of administration.
- Published
- 2011
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