Transcription Factor EB Controls Metabolic Flexibility during Exercise

Abstract

SummaryThe transcription factor EB (TFEB) is an essential component of lysosomal biogenesis and autophagy for the adaptive response to food deprivation. To address the physiological function of TFEB in skeletal muscle, we have used muscle-specific gain- and loss-of-function approaches. Here, we show that TFEB controls metabolic flexibility in muscle during exercise and that this action is independent of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Indeed, TFEB translocates into the myonuclei during physical activity and regulates glucose uptake and glycogen content by controlling expression of glucose transporters, glycolytic enzymes, and pathways related to glucose homeostasis. In addition, TFEB induces the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation. This coordinated action optimizes mitochondrial substrate utilization, thus enhancing ATP production and exercise capacity. These findings identify TFEB as a critical mediator of the beneficial effects of exercise on metabolism.

Fasting Imparts a Switch to Alternative Daily Pathways in Liver and Muscle

“…We analyzed gene targets for hepatic BMAL1 (Koike et al, 2012; Yang et al, 2016), REV-ERBα (Fang et al, 2014), and muscle BMAL1 (Dyar et al, 2013). In addition, we analyzed the targets for hepatic GR (Frijters et al, 2010), CREB (Ravnskjaer et al, 2013; Zhang et al, 2005), FOXO (Haeusler et al, 2014), TFEB (Settembre et al, 2013), PPARα (Montagner et al, 2016), and for muscle GR (Kuo et al, 2012), CREB (Pearen et al, 2009), FOXO (Milan et al, 2015), TFEB (Mansueto et al, 2017), and PPARδ (Gan et al, 2011). We also paralleled muscle histone deacetylase 3 (HDAC3)-target genes from muscle-specific Hdac3 — / — mice, since muscle HDAC3 is primarily regulated by REV-ERBα, while HDAC3 exerts numerous REV-ERBα—independent actions (Hong et al, 2017).…”

“…edu/CREB/) and GEO (GSE47179), respectively, liver specific Foxo1,3,4 —/— liver transcriptome by microarray (Haeusler et al, 2014) from GEO (GSE60527), liver specific PPARα —/— liver transcriptome by microarray (Montagner et al, 2016) from GEO (GSE73299), TFEB-overexpressed liver transcriptome by microarray (Settembre et al, 2013) from GEO (GSE35015), pre- and post-exercise gastrocnemius muscle transcriptome by microarray (Perry et al, 2014) from GEO (GSE61712), muscle specific Bmal1 —/— tibialis anterior muscle transcriptome by microarray (Dyar et al, 2013) from GEO (GSE43071), muscle specific Hdac3 —/— muscle transcriptome by RNA-seq from ‘‘Differentially expressed genes from RNA-seq’’ (Hong et al, 2017), dexamethasone-treated C2C12 myotubes transcriptome by microarray (Kuo et al, 2012) from GEO (GSE28840), cAMP induced muscle transcriptome by microarray (Pearen et al, 2009) from GEO (GSE15793), muscle specific Foxo1,3,4 —/— muscle transcriptome by microarray (Milan et al, 2015) from GEO (GSE52667), PPARδ overexpressing muscle transcriptome by microarray (Gan et al, 2011) from GEO (GSE29055), and TFEB overexpressed muscle transcriptome by microarray (Mansueto et al, 2017) from GEO (GSE62975). Calculation of FC in microarray was carried out by logarithmic normalization unless already logarithmic-transformed.…”

AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance

“…Furthermore, AMPK activates PGC1α (peroxisome proliferator-activated receptor gamma, coactivator 1α), a master regulator of mitochondrial biogenesis, reportedly via direct phosphorylation of PGC1α (Jäger et al, 2007) but also by promoting NAD + -dependent activation of PGC1α by Sirt1 (sirtuin 1) (Cantó et al, 2009). Interestingly, Tfeb, similar to its family member Tfe3, was recently reported to drive mitochondrial biogenesis as well (Mansueto et al, 2017; Wada et al, 2016), which offers the possibility that activation of Tfeb, or Tfe3, might be yet another mechanism by which AMPK can promote the regeneration of mitochondria. In all, AMPK coordinates mitochondrial fission and mitophagy in the acute response to mitochondrial insults, and after sustained energy stress, AMPK promotes transcriptional induction of mitochondrial biogenesis.…”

Metabolic Flexibility in Health and Disease

“…This, in many ways, precipitates an exercise-training response. These changes also pertain to catabolic processes, including autophagy (Mansueto et al, 2017) and other processes to promote organelle and cellular remodeling to enhance overall energy metabolism. Acute exercise induces epigenomic, transcriptomic and proteomic changes in skeletal muscle and WAT, which integrate changes in metabolic pathways to confer greater energy production and better metabolic flexibility for subsequent exercise bouts.…”