RESUMEN
INTRODUCTION: Skeletal muscle oxidative capacity decreases and fatigability increases after spinal cord injury. Transcription factor peroxisome proliferator-activated receptor δ (PPARδ) promotes a more oxidative phenotype. METHODS: We asked whether PPARδ overexpression could ameliorate these deficits in the medial gastrocnemius of spinal cord transected (ST) adult mice. RESULTS: Time-to-peak tension and half-relaxation times were longer in PPARδ-Con and PPARδ-ST compared with littermate wild-type (WT) controls. Fatigue index was 50% higher in PPARδ-Con than WT-Con and 70% higher in the PPARδ-ST than WT-ST. There was an overall higher percent of darkly stained fibers for succinate dehydrogenase in both PPARδ groups. CONCLUSIONS: The results indicate a conversion toward slower, more oxidative, and less fatigable muscle properties with overexpression of PPARδ. Importantly, the elevated fatigue resistance was maintained after ST, suggesting that enhanced PPARδ expression, and possibly small molecule agonists, could ameliorate the increased fatigability routinely observed in chronically paralyzed muscles.
Asunto(s)
Músculo Esquelético/fisiopatología , PPAR alfa/metabolismo , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatología , Animales , Peso Corporal/genética , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fatiga Muscular/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Cadenas Pesadas de Miosina/metabolismo , Tamaño de los Órganos/genética , PPAR alfa/genética , ARN Mensajero/metabolismo , Estadísticas no Paramétricas , Succinato Deshidrogenasa/metabolismoRESUMEN
The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.