ERRs x ERRα x SLC7A1

Mitochondrial energy metabolism is vital for muscle function and is tightly controlled at the transcriptional level, both in the basal state and during adaptive muscle remodeling. The importance of the transcription factors estrogen-related receptors (ERRs) in controlling innate mitochondrial energetics has been recently demonstrated. However, whether different ERR isoforms display distinct functions in glycolytic versus oxidative myofibers is largely unknown. Moreover, their roles in regulating exercise-induced adaptive mitochondrial biogenesis remain unclear. Using muscle-specific single and combinatorial knockout mouse models, we have identified both cooperative and distinct roles of the ERR isoforms ERRα and ERRγ in regulating mitochondrial energy metabolism in different muscles. We demonstrate the essential roles of both these ERRs in mediating adaptive mitochondrial biogenesis in response to exercise training. We further show that PGC1α-induced mitochondrial biogenesis is completely abolished in primary myotubes with ERRα deletion but not ERRγ, highlighting distinct roles of these two isoforms in adaptive mitochondrial remodeling. Mechanistically, we find that both ERRs directly bind to the majority of mitochondrial energetic genes and control their expression, largely through collaborative binding to the same genomic loci. Collectively, our findings reveal critical and direct regulatory roles of ERRα and ERRγ in governing both innate and adaptive mitochondrial energetics in skeletal muscle.

Adult tissue function is dependent on intrinsic factors that mediate stem cell self-renewal and proliferation in response to changes in physiology and the environment. The estrogen-related receptor (ERR) subfamily of orphan nuclear receptors are major transcriptional regulators of metabolism and animal physiology. In mammals, ERRs (NR3B1, NR3B2, NR3B3) have roles in regulating mitochondrial biosynthesis, lipid metabolism, as well as stem cell maintenance. The sole Drosophila ERR ortholog promotes larval growth by establishing a metabolic state during the latter half of embryogenesis. In addition, ERR is required in adult Drosophila males to coordinate glycolytic metabolism with lipid synthesis and within the testis to regulate spermatogenesis gene expression and fertility. Despite extensive work characterizing the role of ERR in Drosophila metabolism, whether ERR has a conserved requirement in regulating stem cell behavior has been understudied. To determine whether ERR regulates stem cell activity in Drosophila, we used the established adult female germline stem cell (GSC) lineage as a model. We found that whole-body ERR knockout in adult females using conditional heat shock-driven FLP-FRT recombination significantly decreases GSC number and glycolytic enzyme expression in GSCs. In addition, we found that ERR activity is required cell-autonomously in the adult female germline for maintenance of GSCs; whereas ERR regulation of GSCs is independent of its activity in adult female adipocytes. Our results highlight an ancient and conserved role for ERRs in the regulation of stem cell self-renewal.

The Estrogen-Related Receptor (ERR) family of nuclear receptors (NRs) serve key roles in coordinating triglyceride (TAG) accumulation with juvenile growth and development. In both insects and mammals, ERR activity promotes TAG storage during the post-embryonic growth phase, with loss-of-function mutations in mouse Esrra and Drosophila melanogaster dERR inducing a lean phenotype. However, the role of insect ERRs in controlling TAG accumulation within adipose tissue remains poorly understood, as nearly all transcriptomic and metabolomic studies have relied on whole animal analyses. Here we address this shortcoming by using tissue-specific approaches to examine the role of dERR in regulating lipid metabolism within the Drosophila larval fat body. We find that dERR autonomously promotes TAG accumulation within fat body cells and regulates expression of genes involved in glycolysis, β-oxidation, and isoprenoid metabolism. As an extension of these results, we not only discovered that dERR mutant fat bodies exhibit decreased expression of known dHNF4 target genes but also found that dHNF4 activity is decreased in dERR mutants. Overall, our findings indicate that dERR plays a multifaceted role in the larval fat body to coordinate lipid storage with carbohydrate metabolism and developmental growth.