The estrogen-related receptors (ERRs) comprise a small group of orphan nuclear receptor transcription factors. The ERRα and ERRγ isoforms play a central role in the regulation of metabolic genes and ...cellular energy metabolism. Although less is known about ERRβ, recent studies have revealed the importance of this isoform in the maintenance of embryonic stem cell pluripotency. Thus, ERRs are essential to many biological processes. The development of several ERR knockout and overexpression models and the application of advanced functional genomics have allowed rapid advancement of our understanding of the physiology regulated by ERR pathways. Moreover, it has enabled us to begin to delineate the distinct programs regulated by ERRα and ERRγ that have overlapping effects on metabolism and growth. The current review primarily focuses on the physiologic roles of ERR isoforms related to their metabolic regulation; therefore, the ERRα and ERRγ are discussed in the greatest detail. We emphasize findings from gain- and loss-of-function models developed to characterize ERR control of skeletal muscle, heart and musculoskeletal physiology. These models have revealed that coordinating metabolic capacity with energy demand is essential for seemingly disparate processes such as muscle differentiation and hypertrophy, innate immune function, thermogenesis, and bone remodeling. Furthermore, the models have revealed that ERRα- and ERRγ-deficiency in mice accelerates progression of pathologic processes and implicates ERRs as etiologic factors in disease. We highlight the human diseases in which ERRs and their downstream metabolic pathways are perturbed, including heart failure and diabetes. While no natural ligand has been identified for any of the ERR isoforms, the potential for using synthetic small molecules to modulate their activity has been demonstrated. Based on our current understanding of their transcriptional mechanisms and physiologic relevance, the ERRs have emerged as potential therapeutic targets for treatment of osteoporosis, muscle atrophy, insulin resistance and heart failure in humans.
•ERRs are orphan nuclear receptor transcription factors.•ERRα and ERRγ play a central role in the regulation of cellular energy metabolism.•ERR signaling pathways are implicated in human diseases.•ERRs are potential therapeutic targets.
Brown adipose tissue (BAT), as the main site of adaptive thermogenesis, exerts beneficial metabolic effects on obesity and insulin resistance. BAT has been previously assumed to contain a homogeneous ...population of brown adipocytes. Utilizing multiple mouse models capable of genetically labeling different cellular populations, as well as single-cell RNA sequencing and 3D tissue profiling, we discovered a brown adipocyte subpopulation with low thermogenic activity coexisting with the classical high-thermogenic brown adipocytes within the BAT. Compared with the high-thermogenic brown adipocytes, these low-thermogenic brown adipocytes had substantially lower Ucp1 and Adipoq expression, larger lipid droplets, and lower mitochondrial content. Functional analyses showed that, unlike the high-thermogenic brown adipocytes, the low-thermogenic brown adipocytes have markedly lower basal mitochondrial respiration, and they are specialized in fatty acid uptake. Upon changes in environmental temperature, the 2 brown adipocyte subpopulations underwent dynamic interconversions. Cold exposure converted low-thermogenic brown adipocytes into high-thermogenic cells. A thermoneutral environment had the opposite effect. The recruitment of high-thermogenic brown adipocytes by cold stimulation is not affected by high-fat diet feeding, but it does substantially decline with age. Our results revealed a high degree of functional heterogeneity of brown adipocytes.
The mitochondrion serves a critical role as a platform for energy transduction, signaling, and cell death pathways relevant to common diseases of the myocardium such as heart failure. This review ...focuses on the molecular regulatory events and downstream effector pathways involved in mitochondrial energy metabolic derangements known to occur during the development of heart failure.
Mitochondrial dysfunction is implicated in skeletal muscle insulin resistance. Syntaxin 4 (STX4) levels are reduced in human diabetic skeletal muscle, and global transgenic enrichment of STX4 ...expression improves insulin sensitivity in mice. Here, we show that transgenic skeletal muscle-specific STX4 enrichment (skmSTX4tg) in mice reverses established insulin resistance and improves mitochondrial function in the context of diabetogenic stress. Specifically, skmSTX4tg reversed insulin resistance caused by high-fat diet (HFD) without altering body weight or food consumption. Electron microscopy of wild-type mouse muscle revealed STX4 localisation at or proximal to the mitochondrial membrane. STX4 enrichment prevented HFD-induced mitochondrial fragmentation and dysfunction through a mechanism involving STX4-Drp1 interaction and elevated AMPK-mediated phosphorylation at Drp1 S637, which favors fusion. Our findings challenge the dogma that STX4 acts solely at the plasma membrane, revealing that STX4 localises at/proximal to and regulates the function of mitochondria in muscle. These results establish skeletal muscle STX4 enrichment as a candidate therapeutic strategy to reverse peripheral insulin resistance.
The heart has a tremendous capacity for ATP generation, allowing it to function as an efficient pump throughout the life of the organism. The adult myocardium uses either fatty acid or glucose ...oxidation as its main energy source. Under normal conditions, the adult heart derives most of its energy through oxidation of fatty acids in mitochondria. However, the myocardium has a remarkable ability to switch between carbohydrate and fat fuel sources so that ATP production is maintained at a constant rate in diverse physiological and dietary conditions. This fuel selection flexibility is important for normal cardiac function. Although cardiac energy conversion capacity and metabolic flux is modulated at many levels, an important mechanism of regulation occurs at the level of gene expression. The expression of genes involved in multiple energy transduction pathways is dynamically regulated in response to developmental, physiological, and pathophysiological cues. This review is focused on gene transcription pathways involved in short- and long-term regulation of myocardial energy metabolism. Much of our knowledge about cardiac metabolic regulation comes from studies focused on mitochondrial fatty acid oxidation. The genes involved in this key energy metabolic pathway are transcriptionally regulated by members of the nuclear receptor superfamily, specifically the fatty acid-activated peroxisome proliferator-activated receptors (PPARs) and the nuclear receptor coactivator, PPARgamma coactivator-1alpha (PGC-1alpha). The dynamic regulation of the cardiac PPAR/PGC-1 complex in accordance with physiological and pathophysiological states will be described.
Aerobic exercise promotes skeletal muscle insulin sensitivity by enhancing glucose uptake and storage and by increasing mitochondrial oxidative capacity. Exercise-responsive transcriptional pathways ...that regulate metabolism represent potential therapeutic targets to combat insulin resistance. The ERRα nuclear receptor regulates mitochondrial oxidative metabolism and is required for the skeletal muscle metabolic response to exercise. In the current study investigated whether ERRα expression is sufficient to drive exercise-induced adaptations in muscle. We generated conditional ERRα transgenic mice that overexpress human ERRα in a tetracycline-inducible and skeletal muscle-specific manner (ERRαMOEiHSA). Dox-induced ERRαMOEiHSA (versus non-induced) mice exhibited reddening in glycolytic muscles, a characteristic of oxidative muscle. Mitochondrial content was increased in these muscles, based on mtDNA quantitation and citrate synthase activity. Consistently, ERRα-overexpressing muscles had higher O2 consumption rates and increased glycogen content. To determine if these metabolic changes altered exercise capacity, run performance was assessed in untrained mice. Dox-induced ERRαMOEiHSA mice tested at constant speed (endurance test) or at increasing speeds (aerobic test) ran longer compared to controls. Post-run blood glucose levels were higher in both testing paradigms, which may be due to greater reliance on β-oxidation and higher basal glycogen stores in ERRα-expressing muscles. Using ChIP and reporters assays we showed that ERRα directly activates gene encoding the catalytic (Ppp1ca) and regulatory subunits (Ppp1r3c) of protein phosphatase 1, involved in hormonal and contractile-activity control of glycogen metabolism. Collectively, these results demonstrate that short-term ERRα activation promotes muscle metabolic adaptations and exercise performance similar to exercise training.
Disclosure
J. Li: None. A. Hamilton: None. J.M. Huss: None.
Funding
American Diabetes Association (1-18-IBS-103 to J.M.H.)
The mitochondrion serves a critical role as a platform for energy transduction, signaling, and cell death pathways relevant to common diseases of the myocardium such as heart failure. This review ...focuses on the molecular regulatory events and downstream effector pathways involved in mitochondrial energy metabolic derangements known to occur during the development of heart failure.
Specialized contractile function and increased mitochondrial number and oxidative capacity are hallmark features of myocyte differentiation. The estrogen‐related receptors (ERRs) can regulate ...mitochondrial biogenesis or mitochondrial enzyme expression in skeletal muscle, suggesting that ERRs may have a role in promoting myogenesis. Therefore, we characterized myogenic programs in primary myocytes isolated from wild‐type (M‐ERRγWT) and muscle‐specific ERRγ–/– (M‐ERRγ–/–) mice. Myotube maturation and number were decreased throughout differentiation in M‐ERRγ–/– primary myocytes, resulting in myotubes with reduced mitochondrial content and sarcomere assembly. Compared with M‐ERRγWT myocytes at the same differentiation stage, the glucose oxidation rate was reduced by 30% in M‐ERRγ–/– myotubes, while medium‐chain fatty acid oxidation was increased by 34% in M‐ERRγ–/– myoblasts and 36% in M‐ERRγ–/– myotubes. Concomitant with increased reliance on mitochondrial β‐oxidation, H2O2 production was significantly increased by 40% in M‐ERRγ–/– myoblasts and 70% in M‐ERRγ–/– myotubes compared to M‐ERRγWT myocytes. ROS activation of FoxO and NF‐κB and their downstream targets, atrogin‐1 and MuRF1, was observed in M‐ERRγ–/– myocytes. The antioxidant N‐acetyl cysteine rescued myotube formation and atrophy gene induction in M‐ERRγ–/– myocytes. These results suggest that loss of ERRγ causes metabolic defects and oxidative stress that impair myotube formation through activation of skeletal muscle atrophy pathways.—Murray, J., Auwerx, J., Huss, J. M. Impaired myogenesis in estrogen‐related receptor γ (ERRγ)‐deficient skeletal myocytes due to oxidative stress. FASEB J. 27, 135–150 (2013). www.fasebj.org
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