RESUMEN
How breast cancer and its treatments affect skeletal muscle is not well defined. To address this question, we assessed skeletal muscle structure and protein expression in 13 women who were diagnosed with breast cancer and receiving adjuvant chemotherapy following tumor resection and 12 nondiseased controls. Breast cancer patients showed reduced single-muscle fiber cross-sectional area and fractional content of subsarcolemmal and intermyofibrillar mitochondria. Drugs commonly used in breast cancer patients (doxorubicin and paclitaxel) caused reductions in myosin expression, mitochondrial loss, and increased reactive oxygen species (ROS) production in C2C12 murine myotube cell cultures, supporting a role for chemotherapeutics in the atrophic and mitochondrial phenotypes. Additionally, concurrent treatment of myotubes with the mitochondrial-targeted antioxidant MitoQ prevented chemotherapy-induced myosin depletion, mitochondrial loss, and ROS production. In patients, reduced mitochondrial content and size and increased expression and oxidation of peroxiredoxin 3, a mitochondrial peroxidase, were associated with reduced muscle fiber cross-sectional area. Our results suggest that chemotherapeutics may adversely affect skeletal muscle in patients and that these effects may be driven through effects of these drugs on mitochondrial content and/or ROS production.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Caquexia/genética , Atrofia Muscular/genética , Peroxiredoxina III/genética , Anciano , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Caquexia/inducido químicamente , Caquexia/patología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Persona de Mediana Edad , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/inducido químicamente , Atrofia Muscular/patología , Miosinas/genética , Miosinas/metabolismo , Compuestos Organofosforados/farmacología , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/farmacologíaRESUMEN
Endoplasmic reticulum (ER) stress-induced unfolded protein response plays a critical role in inflammatory diseases, including allergic airway disease. However, the benefits of inhibiting ER stress in the treatment of allergic airway disease are not well known. Herein, we tested the therapeutic potential of a chemical chaperone, tauroursodeoxycholic acid (TUDCA), in combating allergic asthma, using a mouse model of house dust mite (HDM)-induced allergic airway disease. TUDCA was administered during the HDM-challenge phase (preventive regimen), after the HDM-challenge phase (therapeutic regimen), or therapeutically during a subsequent HDM rechallenge (rechallenge regimen). In the preventive regimen, TUDCA significantly decreased HDM-induced inflammation, markers of ER stress, airway hyperresponsiveness (AHR), and fibrosis. Similarly, in the therapeutic regimen, TUDCA administration efficiently decreased HDM-induced airway inflammation, mucus metaplasia, ER stress markers, and AHR, but not airway remodeling. Interestingly, TUDCA administered therapeutically in the HDM rechallenge regimen markedly attenuated HDM-induced airway inflammation, mucus metaplasia, ER stress markers, methacholine-induced AHR, and airway fibrotic remodeling. These results indicate that the inhibition of ER stress in the lungs through the administration of chemical chaperones could be a valuable strategy in the treatment of allergic airway diseases.
Asunto(s)
Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Asma/tratamiento farmacológico , Ácido Tauroquenodesoxicólico/farmacología , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Animales , Antiasmáticos/uso terapéutico , Antiinflamatorios/uso terapéutico , Asma/inmunología , Evaluación Preclínica de Medicamentos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/inmunología , Femenino , Ratones Endogámicos C57BL , Pyroglyphidae/inmunología , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/inmunología , Ácido Tauroquenodesoxicólico/uso terapéuticoRESUMEN
Three family lines of fast growing transgenic rohu Labeo rohita (rohu) were generated by electroporated-sperm-mediated transfer of the vectors harboring CMV promoter or grass carp beta-actin promoter fused to endogenous rohu GH (rGH) cDNA. The gene transfer efficiency was 25%. The transgenic rohu (family line 1) with CMV promoter showed a growth enhancement of four times normal size, whereas those (family lines 2 and 3) generated with beta-actin promoter grew 4.5 and 5.8 times faster than their respective control siblings. Southern analysis confirmed the transgene extrachromosomal (Te) persistence until the 60th week in family 1. The individuals of family lines 2 and 3, however, showed integration (Ti), as well as persistence as extrachromosomal copies (Te) until the age of 30 weeks. Mosaicism of the transgene was shown at the levels of its presence and expression. The ectopic expression of rGH mRNA was confirmed by RT-PCR. Feeding experiments revealed that the transgenic rohu ate food at a lower rate but grew more efficiently than their control siblings.