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The human genome is generally organized into stable chromosomes, and only tumor cells are known to accumulate kilobase (kb)-sized extrachromosomal circular DNA elements (eccDNAs). However, it must be expected that kb eccDNAs exist in normal cells as a result of mutations. Here, we purify and sequence eccDNAs from muscle and blood samples from 16 healthy men, detecting ~100,000 unique eccDNA types from 16 million nuclei. Half of these structures carry genes or gene fragments and the majority are smaller than 25 kb. Transcription from eccDNAs suggests that eccDNAs reside in nuclei and recurrence of certain eccDNAs in several individuals implies DNA circularization hotspots. Gene-rich chromosomes contribute to more eccDNAs per megabase and the most transcribed protein-coding gene in muscle, TTN (titin), provides the most eccDNAs per gene. Thus, somatic genomes are rich in chromosome-derived eccDNAs that may influence phenotypes through altered gene copy numbers and transcription of full-length or truncated genes. Somatic cells can accumulate structural variations such as deletions. Here, Møller et al. show that normal human cells generate large extrachromosomal circular DNAs (eccDNAs), most likely the products of excised DNA, that can be transcriptionally active and, thus, may have phenotypic consequences.

The aim of the present study was to examine the role of PGC-1α in intensity dependent exercise and exercise training-induced metabolic adaptations in mouse skeletal muscle. Whole body PGC-1α knockout (KO) and littermate wildtype (WT) mice performed a single treadmill running bout at either low intensity (LI) for 40 min or moderate intensity (MI) for 20 min. Blood and quadriceps muscles were removed either immediately after exercise or at 3h or 6h into recovery from exercise and from resting controls. In addition PGC-1α KO and littermate WT mice were exercise trained at either low intensity (LIT) for 40 min or at moderate intensity (MIT) for 20 min 2 times pr. day for 5 weeks. In the first and the last week of the intervention period, mice performed a graded running endurance test. Quadriceps muscles were removed before and after the training period for analyses. The acute exercise bout elicited intensity dependent increases in LC3I and LC3II protein and intensity independent decrease in p62 protein in skeletal muscle late in recovery and increased LC3II with exercise training independent of exercise intensity and volume in WT mice. Furthermore, acute exercise and exercise training did not increase LC3I and LC3II protein in PGC-1α KO. In addition, exercise-induced mRNA responses of PGC-1α isoforms were intensity dependent. In conclusion, these findings indicate that exercise intensity affected autophagy markers differently in skeletal muscle and suggest that PGC-1α regulates both acute and exercise training-induced autophagy in skeletal muscle potentially in a PGC-1α isoform specific manner.

Lifelong regular physical activity is associated with reduced risk of type 2 diabetes (T2D), maintenance of muscle mass and increased metabolic capacity. However, little is known about epigenetic mechanisms that might contribute to these beneficial effects in aged individuals. We investigated the effect of lifelong physical activity on global DNA methylation patterns in skeletal muscle of healthy aged men, who had either performed regular exercise or remained sedentary their entire lives (average age 62 years). DNA methylation was significantly lower in 714 promoters of the physically active than inactive men while methylation of introns, exons and CpG islands was similar in the two groups. Promoters for genes encoding critical insulin-responsive enzymes in glycogen metabolism, glycolysis and TCA cycle were hypomethylated in active relative to inactive men. Hypomethylation was also found in promoters of myosin light chain, dystrophin, actin polymerization, PAK regulatory genes and oxidative stress response genes. A cluster of genes regulated by GSK3β-TCF7L2 also displayed promoter hypomethylation. Together, our results suggest that lifelong physical activity is associated with DNA methylation patterns that potentially allow for increased insulin sensitivity and a higher expression of genes in energy metabolism, myogenesis, contractile properties and oxidative stress resistance in skeletal muscle of aged individuals.

Moderately trained male subjects (mean age 25 years; range 19–33 years) completed an 8‐week exercise training intervention consisting of continuous moderate cycling at 157 ± 20 W for 60 min (MOD; n = 6) or continuous moderate cycling (157 ± 20 W) interspersed by 30‐sec sprints (473 ± 79 W) every 10 min (SPRINT; n = 6) 3 days per week. Sprints were followed by 3:24 min at 102 ± 17 W to match the total work between protocols. A muscle biopsy was obtained before, immediately and 2 h after the first training session as well as at rest after the training session. In both MOD and SPRINT, skeletal muscle AMPKThr172 and ULKSer317 phosphorylation was elevated immediately after exercise, whereas mTORSer2448 and ULKSer757 phosphorylation was unchanged. Two hours after exercise LC3I, LC3II and BNIP3 protein content was overall higher than before exercise with no change in p62 protein. In MOD, Beclin1 protein content was higher immediately and 2 h after exercise than before exercise, while there were no differences within SPRINT. Oxphos complex I, LC3I, BNIP3 and Parkin protein content was higher after the training intervention than before in both groups, while there was no difference in LC3II and p62 protein. Beclin1 protein content was higher after the exercise training intervention only in MOD. Together this suggests that exercise increases markers of autophagy in human skeletal muscle within the first 2 h of recovery and 8 weeks of exercise training increases the capacity for autophagy and mitophagy regulation. Hence, the present findings provide evidence that exercise and exercise training regulate autophagy in human skeletal muscle and that this in general was unaffected by interspersed sprint bouts. A single exercise bout seems to increase autophagosome number, and exercise training seems to increase the capacity for autophagy and mitophagy regulation in human skeletal muscle. In addition, the present findings provide evidence that these effects are unaffected by interspersed sprint bouts, although regulation of some autophagy markers appear to be inhibited by short lasting high‐intensity bouts.

eccDNA is a driver of many cancers and a potential intermediate in other age-related disorders. However, little is known about the mechanisms underlying eccDNA formation in healthy tissue and how aging affects these processes. Here, we present an atlas of eccDNA across seven tissues of male mice spanning four ages. EccDNA correlates with open chromatin characterized by signatures of H3K27ac and H3K4me1. Additionally, the mutational load of eccDNA on genes correlates with tissue-specific transcription and increases logarithmically as a function of transcript level. Still, a population of intron-dense genes with many splice forms remains sheltered from eccDNA formation. We also find that the total number of eccDNA molecules does not increase as mice age, unlike other types of mutations. Our data reveal a link between eccDNA formation and transcript level that may drive gene architecture in mammals. Extrachromosomal circular DNA (eccDNA) can drive cancer and other age-related diseases. Here, Liang et al. present an atlas of eccDNA in mammals, and demonstrate that the number of eccDNA increases logarithmically as a function of transcript levels.

The liver and adipose tissue are important tissues in whole-body metabolic regulation during fasting. Interleukin 6 (IL-6) is a cytokine shown to be secreted from contracting muscle in humans and suggested to signal to the liver and adipose tissue. Furthermore, skeletal muscle IL-6 has been proposed to play a role during fasting. Therefore the aim of the present study was to investigate the role of skeletal muscle IL-6 in the regulation of substrate production in the liver and adipose tissue during fasting. Male skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice and littermate floxed (control) mice fasted for 6 or 18 h (6 h fasting or 18 h fasting) with corresponding fed control groups (6 h fed or 18 h fed) and liver and adipose tissue were quickly obtained. Plasma β-hydroxybutyrate increased and hepatic glucose, lactate and glycogen decreased with fasting. In addition, fasting increased phosphoenolpyruvate carboxykinase protein and phosphorylation of pyruvate dehydrogenase (PDH) in the liver as well as hormone-sensitive lipase (HSL)Ser660 and HSLSer563 phosphorylation, PDH phosphorylation, adipose triglyceride lipase phosphorylation and perilipin phosphorylation and protein content in adipose tissue without any effect of lack of skeletal muscle IL-6. In conclusion, fasting induced regulation of enzymes in adipose tissue lipolysis and glyceroneogenesis as well as regulation of hepatic gluconeogenic capacity and hepatic substrate utilization in mice. However, skeletal muscle IL-6 was not required for these fasting-induced effects, but had minor effects on markers of lipolysis and glyceroneogenesis in adipose tissue as well as markers of hepatic gluconeogenesis in the fed state.

White adipose tissue is a major energy reserve for the body and is essential for providing fatty acids for other tissues when needed. Skeletal muscle interleukin-6 (IL-6) has been shown to be secreted from the working muscle and has been suggested to signal to adipose tissue and enhance lipolysis. The aim of the present study was to investigate the role of skeletal muscle IL-6 in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) lipolysis and glyceroneogenesis with prolonged moderate-intensity exercise and high-intensity exercise in mice. Female inducible muscle-specific IL-6 knockout (IL-6 iMKO) mice and littermate control (Floxed) mice performed a single exercise bout for either 120 min at 16 m/min and 10° slope (moderate intensity) or 30 min at 20 m/min and 10° slope (high intensity), or they remained rested (rest). Visceral and subcutaneous adipose tissues, quadriceps muscles, and blood were quickly obtained. Plasma IL-6 increased in Floxed mice but not in IL-6 iMKO mice with high-intensity exercise. VAT signal transducer and activator of transcription (STAT)3Tyr705 phosphorylation was lower, and VAT hormone-sensitive lipase (HSL)Ser563 phosphorylation was higher in IL-6 iMKO mice than in Floxed mice at rest. Furthermore, HSLSer563 and HSLSer660 phosphorylation increased in VAT and phosphoenolpyruvate carboxykinase protein decreased in SAT with moderate-intensity exercise in both genotypes. On the other hand, both exercise protocols increased pyruvate dehydrogenaseSer232 phosphorylation in VAT only in IL-6 iMKO mice and decreased tumor necrosis factor-α messenger RNA in SAT and VAT only in Floxed mice. In conclusion, the present findings suggest that skeletal muscle IL-6 regulates markers of lipolysis in VAT in the basal state and pyruvate availability for glyceroneogenesis in VAT with exercise. Moreover, skeletal muscle IL-6 may contribute to exercise-induced anti-inflammatory effects in SAT and VAT.

Expression of brown adipose tissue (BAT) associated proteins like uncoupling protein 1 (UCP1) in inguinal WAT (iWAT) has been suggested to alter iWAT metabolism. The aim of this study was to investigate the role of interleukin-6 (IL-6) in exercise training and cold exposure-induced iWAT UCP1 expression. The effect of daily intraperitoneal injections of IL-6 (3 ng/g) in C57BL/6 mice for 7 days on iWAT UCP1 expression was examined. In addition, the expression of UCP1 in iWAT was determined in response to 3 days of cold exposure (4°C) and 5 weeks of exercise training in wild type (WT) and whole body IL-6 knockout (KO) mice. Repeated injections of IL-6 in C57BL/6 mice increased UCP1 mRNA but not UCP1 protein content in iWAT. Cold exposure increased iWAT UCP1 mRNA content similarly in IL-6 KO and WT mice, while exercise training increased iWAT UCP1 mRNA in WT mice but not in IL-6 KO mice. Additionally, a cold exposure-induced increase in iWAT UCP1 protein content was blunted in IL-6 KO mice, while UCP1 protein content in iWAT was lower in both untrained and exercise trained IL-6 KO mice than in WT mice. In conclusion, repeated daily increases in plasma IL-6 can increase iWAT UCP1 mRNA content and IL-6 is required for an exercise training-induced increase in iWAT UCP1 mRNA content. In addition IL-6 is required for a full induction of UCP1 protein expression in response to cold exposure and influences the UCP1 protein content iWAT of both untrained and exercise trained animals.

An acute bout of exercise imposes a major challenge on whole-body metabolism and metabolic adjustments are needed in multiple tissues during recovery to reestablish metabolic homeostasis. It is currently unresolved how this regulation is orchestrated between tissues. This study was undertaken to clarify the role of skeletal muscle derived interleukin 6 (IL-6) in the coordination of the metabolic responses during recovery from acute exercise. Skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate Control mice were rested or ran on a treadmill for 2h. Plasma, skeletal muscle, liver and adipose tissue were obtained after 6 and 10h of recovery. Non-exercised IL-6 MKO mice had higher plasma lactate and lower plasma non-esterified fatty acids than Controls. The activity of pyruvate dehydrogenase in the active form was, in skeletal muscle, higher in IL-6 MKO mice than Controls in non-exercised mice and 6h after exercise. IL-6 MKO mice had lower glucose transporter 4 protein content in inguinal adipose tissue (WAT) than Control in non-exercised mice and 10h after treadmill running. Epididymal WAT hormone sensitive lipase phosphorylation and inguinal WAT mitogen activated kinase P38 phosphorylation were higher in IL-6 MKO than Control mice 6h after exercise. These findings indicate that skeletal muscle IL-6 may play an important role in the regulation of substrate utilization in skeletal muscle, basal and exercise-induced adaptations in adipose tissue glucose uptake and lipolysis during recovery from exercise. Together this indicates that skeletal muscle IL-6 contributes to reestablishing metabolic homeostasis during recovery from exercise by regulating WAT and skeletal muscle metabolism.