Cardiac protection and transcriptional responses to voluntary activity in mice

Activity or exercise improves longevity and limits severity of chronic illness, including cardiovascular disease. However, mechanisms underlying the beneficial effects of exercise on cardiac protection are incompletely defined. PURPOSE: To test the hypothesis that the cardio-protective effect of exercise will increase with time, we studied the impact of voluntary running on resistance of hearts to myocardial infarction (ischaemia-reperfusion; I/R). METHODS: 8 week old wild-type C57B1/6 male mice were provided with freely rotating or locked running wheels for 2, 7, 14 or 28 days. Hearts were removed and perfused in a Langendorff mode, and responses to 20 min ischaemia/40 min reperfusion were assessed. Sub-sets of hearts were removed at 7 days and assessed for transcriptional responses via cDNA microarray. RESULTS: Mice increased running distance, from 2 km/day at 2 days up to 10 km/day after 28 days. Voluntary running improved I/R tolerance, increasing contractile recovery 46.2±3% vs 73.1±5% and limiting diastolic dysfunction by reducing diastolic pressure 24.6 ±2 vs 16.8±3 mmHg (p ≤ 0.05, control vs run-trained) after 28 days. Protection was expressed as early as 7 days and appeared to plateau from 14-28 days. Array analysis identified over 800 modified genes (<5% FDR), most induced vs. repressed. Pathway analysis identified major shifts in grouping related to cell movement/contraction (myocyte structure/contraction, mechanotransduction), immune responses, and cell signalling (PI3-kinase and growth factor signals). CONCLUSIONS: Even brief episodes (7 days) of voluntary running altered the phenotype and improved disease resistance of the mammalian myocardium. The protective effect of exercise on the myocardium was increased with days running. Early transcriptional modifications to control of cell movement, growth and structure may play a key role in establishing this effect.