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Circadian clock confers temporal control in metabolism, with its disruption leading to the development of insulin resistance. Metabolic substrate utilization in skeletal muscle is coordinated with diurnal nutrient cycles. However, whether the molecular clock is involved in this coordination is largely unknown. Using a myocyte-selective genetic ablation mouse model of the essential clock activator Bmal1, here we identify muscle-intrinsic clock as a sensor of feeding cues to orchestrate skeletal muscle oxidation required for global nutrient flux. Bmal1 in skeletal muscle responds robustly to feeding in vivo and insulin induces its expression. Muscle Bmal1 deficiency impaired the transcriptional control of glucose metabolic pathway, resulting in markedly attenuated glucose utilization and fasting hyperglycemia. Notably, the loss of Bmal1 response to feeding abolished fasting-to-feeding metabolic fuel switch from fatty acids to glucose in skeletal muscle, leading to the activation of energy-sensing pathways for fatty acid oxidation. These altered metabolic substrate oxidations in Bmal1-deficient muscle ultimately depleted circulating lipid levels that prevented hepatic steatosis. Collectively, our findings highlight the key role of the metabolic-sensing function of skeletal muscle clock in partitioning nutrient flux between muscle and liver to maintain whole-body lipid and glucose homeostasis.

Rev-erbα is a ligand-dependent nuclear receptor and a key repressor of the molecular clock transcription network. Accumulating evidence indicate that the circadian clock machinery governs diverse biological processes in skeletal muscle, including muscle growth, repair and mass maintenance. The physiological function of Rev-erbα in myogenic regulation remains largely unknown. Here we show that Rev-erbα exerts cell-autonomous inhibitory effects on proliferation and differentiation of myogenic precursor cells, and these actions concertedly inhibit muscle regeneration in vivo. Mechanistic studies reveal Rev-erbα direct transcriptional control of two major myogenic mechanisms, proliferative pathway and the Wnt signaling cascade. Consistent with this finding, primary myoblasts lacking Rev-erbα display significantly enhanced proliferative growth and myogenic progression. Furthermore, pharmacological activation of Rev-erbα activity attenuates, whereas its inhibition by an antagonist promotes these processes. Notably, upon muscle injury, the loss-of-function of Rev-erbα in vivo augmented satellite cell proliferative expansion and regenerative progression during regeneration. Collectively, our study identifies Rev-erbα as a novel inhibitory regulator of myogenic progenitor cell properties that suppresses postnatal myogenesis. Pharmacological interventions to dampen Rev-erbα activity may have potential utilities to enhance regenerative capacity in muscle diseases.

The circadian clock exerts temporal control in metabolism and its disruption leads to the development of diabetes and obesity. Tissue-intrinsic clock circuits are integral components of global metabolic homeostasis, although how they sense nutrient signals to orchestrate metabolic flux is not clear. Skeletal muscle is major site for metabolic substrate oxidation, and its utilization of glucose and fatty acid depends on availability of nutrients accompanying feeding-fasting transitions. Interestingly, nearly 30% of rhythmic transcripts in skeletal muscle belongs to metabolism. By generating a mouse model with myocyte-selective ablation of the clock transcription activator Bmal1, here we show that cell-autonomous muscle clock plays an essential role in coordinating nutrient utilization with feeding-fasting induced cycles. Bmal1 in skeletal muscle was robustly induced by feeding, and its loss markedly impaired feeding-induced switch to glucose metabolism from fatty acid utilization. As a result, Bmal1-deficient muscle displays nearly 50% reduction of glucose oxidation whereas fatty acid oxidation was enhanced, resembling a constant fasting state. This metabolic shift was accompanied by muscle fiber type switching to an oxidative phenotype, and led to a remarkable resistance to hepatic lipid accumulation induced by prolonged fasting or high-fat diet feeding. In contrast, systemic fasting glucose levels in muscle Bmal1-deficient mice was elevated, which is due to a failure of suppressing hepatic glucose output as revealed by hyperinsulinemic-euglycemic glucose clamp study. Collectively, our results reveal a novel function of the Bmal1-driven muscle clock as a key metabolic sensor that coordinates metabolic fuel oxidation with oscillatory nutrient availability in fasting-feeding cycles. This temporal mechanism in orchestrating global nutrient flux may contribute to metabolic abnormalities induced by circadian misalignment. Disclosure K. Ma: None. S. Chatterjee: None. H. Yin: None.

Aberrant mitochondrial energy transfer underlies prevalent chronic health conditions, including cancer, cardiovascular, and neurodegenerative diseases. Mitochondrial transplantation represents an innovative strategy aimed at restoring favorable metabolic phenotypes in cells with dysfunctional energy metabolism. While promising, significant barriers to in vivo translation of this approach abound, including limited cellular uptake and recognition of mitochondria as foreign. The objective is to functionalize isolated mitochondria with a biocompatible polymer to enhance cellular transplantation and eventual in vivo applications. Herein, it is demonstrated that grafting of a polymer conjugate composed of dextran with triphenylphosphonium onto isolated mitochondria protects the organelles and facilitates cellular internalization compared with uncoated mitochondria. Importantly, mitochondrial transplantation into cancer and cardiovascular cells has profound effects on respiration, mediating a shift toward improved oxidative phosphorylation, and reduced glycolysis. These findings represent the first demonstration of polymer functionalization of isolated mitochondria, highlighting a viable strategy for enabling clinical applications of mitochondrial transplantation.

The molecular clock is intimately linked with metabolic regulation and brown adipose tissue plays a key role in energy homeostasis. However, whether the cell-intrinsic clock machinery participates in brown adipocyte development is unknown. Here we show that Bmal1, the essential clock transcription activator, inhibits brown adipogenesis to adversely impact brown fat formation and thermogenic capacity. Global ablation of Bmal1 in mice increases brown fat mass and cold tolerance, while adipocyte-selective inactivation of Bmal1 recapitulates these effects and demonstrates its cell-autonomous role in brown adipocyte formation. Further loss- and gain-of function studies in mesenchymal precursors and committed brown progenitors reveal that Bmal1 inhibits brown adipocyte lineage commitment and terminal differentiation. Mechanistically, Bmal1 inhibits brown adipogenesis through direct transcriptional control of key components of the TGF-β pathway together with reciprocally altered BMP signaling, and activation of TGF-β, or blockade of BMP pathways, suppresses enhanced differentiation in Bmal1-deficient brown adipocytes. Collectively, our study demonstrates a novel temporal regulatory mechanism in fine-tuning brown adipocyte lineage progression to impact brown fat formation and thermogenic regulation, which may be targeted therapeutically to combat obesity.

The ICP34.5 gene from HSV-2 strain 333 was cloned and, when expressed in Vero cells, enhanced the efficiency and extent of glycoprotein processing of glycoprotein C (gC1), a representative viral glycoprotein, during infection with HSV-1 SP7. The ICP34.5 from HSV-1 SP7 limits the extent and efficiency of viral glycoprotein processing. The ability of the HSV-2 ICP34.5 protein to enhance the efficiency and extent of HSV-1 SP7 glycoprotein processing indicates that modulation of viral glycoprotein processing is also a property of the HSV-2 ICP34.5 protein.