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Regularly performed endurance training has many beneficial effects on health and skeletal muscle function, and can be used to prevent and treat common diseases e.g. cardiovascular disease, type II diabetes and obesity. The molecular adaptation mechanisms regulating these effects are incompletely understood. To date, global transcriptome changes in skeletal muscles have been studied at the gene level only. Therefore, global isoform expression changes following exercise training in humans are unknown. Also, the effects of repeated interventions on transcriptional memory or training response have not been studied before. In this study, 23 individuals trained one leg for three months. Nine months later, 12 of the same subjects trained both legs in a second training period. Skeletal muscle biopsies were obtained from both legs before and after both training periods. RNA sequencing analysis of all 119 skeletal muscle biopsies showed that training altered the expression of 3,404 gene isoforms, mainly associated with oxidative ATP production. Fifty-four genes had isoforms that changed in opposite directions. Training altered expression of 34 novel transcripts, all with protein-coding potential. After nine months of detraining, no training-induced transcriptome differences were detected between the previously trained and untrained legs. Although there were several differences in the physiological and transcriptional responses to repeated training, no coherent evidence of an endurance training induced transcriptional skeletal muscle memory was found. This human lifestyle intervention induced differential expression of thousands of isoforms and several transcripts from unannotated regions of the genome. It is likely that the observed isoform expression changes reflect adaptational mechanisms and processes that provide the functional and health benefits of regular physical activity., Author Summary Skeletal muscle is the most abundant tissue of the healthy human body. It is also highly adaptable to different environmental stimuli, e.g. regular exercise. Exercise training improves overall health and muscle function, and can be used to prevent and treat several common diseases e.g. cardiovascular disease and type II diabetes. Therefore, it is of great importance to understand the molecular mechanisms behind adaptation processes in human skeletal muscle. In this study, we show that different expression variants from the same gene can be regulated in different directions with training, implicating alternative protein functions from one single gene. Such findings are emblematic of the complex mechanisms regulating the effects of training. We also find that training changes the activity of functionally unknown parts of the genome, with the potential for new proteins involved in the health-enhancing effects of exercise. Additionally, our results challenge the belief of a skeletal muscle memory, where previous training can affect the response to a subsequent training period. Overall, we provide understanding of the skeletal muscle biology and novel insights into the mechanisms behind the massive benefits of regular exercise on the human skeletal muscle transcriptome, inspiring further studies for deeper investigation.