Transcriptional and metabolic remodelling induced by exercise and obesity in mouse skeletal muscle

Metabolic diseases (e.g. type 2 diabetes) are among the main causes of death and economical burden worldwide. Physical inactivity and over-nutrition are key risk factors of these pathologies, with impaired skeletal muscle gene transcription and metabolic function proposed as key etiological factors. Here, we have explored this possibility in skeletal muscle from mice fed a control or high fat diet (HFD), both pre- and 3h post-exercise. Under basal conditions, HFD increased the expression of genes promoting fatty acid (FA) catabolism, while those controlling FA anabolism were decreased. Consistently, Acetyl-CoA and metabolites related with FA metabolism were higher in muscle of HFD mice. Transcription of genes related with muscle contractility was also impaired by HFD, thus consistent with lower exercise performance observed in HFD mice. Acute exercise increased the expression of genes controlling transcription and muscle development/remodelling, whereas this response was attenuated by HFD. In HFD mice, up-regulated genes were mainly associated with processes modulating signal transduction, while down-regulated genes were involved in cellular integrity and growth. The muscle metabolome was mainly remodelled by HFD, with exercise having a less dramatic effect. Collectively, these data suggest that HFD enhances FA oxidation, impairs function/integrity and attenuates exercise-mediated adaptations in skeletal muscle. Therefore, the combination of dietary/exercise manipulation with next-generation sequencing and metabolomics provides an integrative platform to study skeletal muscle transcriptional and metabolic networks in the context of health and disease.