RESUMEN
Although most literature suggests a relative protection of slow twitch muscle with aging, there is limited data in senescence when muscle atrophy and functional decline markedly accelerate. To address this issue we examined age-related changes in muscle mass, contractile function, mitochondrial enzyme activities, and myosin heavy chain (MHC) expression in the slow twitch soleus (Sol) and fast twitch gastrocnemius (Gas) muscle of young adult (YA) and senescent (SEN) rats. Muscle mass declined between YA and SEN in the Sol by 35% compared to 55% in the Gas muscle. After normalizing for muscle mass, tetanic force per g of muscle declined by 58% in Sol and by 36% in Gas muscle. Time-to-peak tension was increased only in the Gas (30%), whereas time-to-half relaxation was increased by 70% in Sol and 51% in Gas. Citrate synthase and complex IV activity declined in homogenates of Sol (30-36%) and red oxidative region of Gas (46-51%), but not white glycolytic region of Gas. Strikingly, the shift away from the dominant adult MHC isoform with aging was much greater in Sol (fibers positive for MHC fast: 11+/-2% in YA versus 36+/-3% in SEN) than in Gas (fibers positive for MHC slow: 12+/-1% in YA versus 26+/-3% in SEN) muscle. Collectively, these results show that the slow twitch Sol muscle undergoes large phenotypic alterations in very old age and for several measures (tetanic tension per g, time-to-half relaxation and shift in adult MHC expression) that is of greater magnitude than fast twitch muscle, underscoring the importance of including age-related changes in slow twitch muscle in seeking potential treatments for sarcopenia.
Asunto(s)
Fibras Musculares de Contracción Lenta/fisiología , Sarcopenia/epidemiología , Animales , Ciclo del Ácido Cítrico , Modelos Animales de Enfermedad , Estimulación Eléctrica , Cinética , Complejo Mayor de Histocompatibilidad , Mitocondrias/metabolismo , Mitocondrias Musculares/enzimología , Contracción Muscular/fisiología , Fibras Musculares de Contracción Lenta/patología , Músculo Esquelético/anatomía & histología , Músculo Esquelético/crecimiento & desarrollo , Cadenas Pesadas de Miosina/genética , Ratas , Ratas Endogámicas BN , Ratas Endogámicas F344 , Sarcopenia/patologíaRESUMEN
In this report it is demonstrated for the first time that rabies-G envelope of the rabies virus is sufficient to confer retrograde axonal transport to a heterologous virus/vector. After delivery of rabies-G pseudotyped equine infectious anaemia virus (EIAV) based vectors encoding a marker gene to the rat striatum, neurons in regions distal from but projecting to the injection site, such as the dopaminergic neurons of the substantia nigra pars compacta, become transduced. This retrograde transport to appropriate distal neurons was also demonstrated after delivery to substantia nigra, hippocampus and spinal cord and did not occur when vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped vectors were delivered to these sites. In addition, peripheral administration of rabies-G pseudotyped vectors to the rat gastrocnemius muscle leads to gene transfer in motoneurons of lumbar spinal cord. In contrast the same vector pseudotyped with VSV-G transduced muscle cells surrounding the injection site, but did not result in expression in any cells in the spinal cord. Long-term expression was observed after gene transfer in the nervous system and a minimal immune response which, together with the possibility of non-invasive administration, greatly extends the utility of lentiviral vectors for gene therapy of human neurological disease.
Asunto(s)
Antígenos Virales , Transporte Axonal/fisiología , Glicoproteínas/genética , Virus de la Anemia Infecciosa Equina/fisiología , Glicoproteínas de Membrana , Sistema Nervioso/virología , Virus de la Rabia/fisiología , Rabia/virología , Proteínas del Envoltorio Viral/genética , Animales , Células Cultivadas , Cuerpo Estriado/virología , Cartilla de ADN/química , ADN Viral/análisis , Técnicas de Transferencia de Gen , Vectores Genéticos , Técnicas para Inmunoenzimas , Operón Lac/fisiología , Masculino , Ratones , Reacción en Cadena de la Polimerasa , Ratas , Ratas EndogámicasAsunto(s)
Mitocondrias Musculares , Tripsina/farmacología , Adenosina Difosfato/farmacología , Animales , Fraccionamiento Celular , Centrifugación por Gradiente de Densidad , Microscopía Electrónica , Mitocondrias Musculares/análisis , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/metabolismo , Músculos/efectos de los fármacos , Consumo de Oxígeno , Fosfolípidos/análisis , Proteínas/análisis , RatasRESUMEN
1. Five glucocorticoids, when administered daily to rats for 5-7 days at a dosage of 5mg/kg, were in the following order of effectiveness with respect to their ability to decrease the weight gain of whole animals and the vastus lateralis, vastus medialis and gluteus medius muscles: corticosteroneAsunto(s)
Glucocorticoides/farmacología
, Mitocondrias Musculares/efectos de los fármacos
, Músculos/metabolismo
, Ribosomas/efectos de los fármacos
, Aminoácidos/metabolismo
, Animales
, Betametasona/farmacología
, Peso Corporal/efectos de los fármacos
, Isótopos de Carbono
, Corticosterona/farmacología
, Dexametasona/farmacología
, Relación Dosis-Respuesta a Droga
, Leucina/metabolismo
, Masculino
, Músculos/citología
, Músculos/efectos de los fármacos
, Oxidación-Reducción
, Prednisolona/farmacología
, Ratas
, Triamcinolona/farmacología
, Triamcinolona Acetonida/farmacología
, Tritio