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We have previously found that in utero exposure to excess maternal cortisol (1 mg/kg/day) in late gestation increases the incidence of stillbirth during labor and produces fetal bradycardia at birth. In the interventricular septum, mitochondrial DNA (mt-DNA) was decreased, and transcriptomics and metabolomics were consistent with altered mitochondrial metabolism. The present study uses transcriptomics to model effects of increased maternal cortisol on fetal biceps femoris. Transcriptomic modeling revealed that pathways related to mitochondrial metabolism were downregulated, whereas pathways for regulation of reactive oxygen species and activation of the apoptotic cascade were upregulated. Mt-DNA and the protein levels of cytochrome C were significantly decreased in the biceps femoris. RT-PCR validation of the pathways confirmed a significant decrease in SLC2A4 mRNA levels and a significant increase in PDK4, TXNIP, ANGPTL4 mRNA levels, suggesting that insulin sensitivity of the biceps femoris muscle may be reduced in cortisol offspring. We also tested for changes in gene expression in diaphragm by rt-PCR. PDK4, TXNIP, and ANGPTL4 mRNA were also increased in the diaphragm, but SLC2A4, cytochrome C protein, and mt-DNA were unchanged. Comparison of the change in gene expression in biceps femoris to that in cardiac interventricular septum and left ventricle showed few common genes and little overlap in specific metabolic or signaling pathways, despite reduction in mt-DNA in both heart and biceps femoris. Our results suggest that glucocorticoid exposure alters expression of nuclear genes important to mitochondrial activity and oxidative stress in both cardiac and skeletal muscle tissues, but that these effects are tissue-specific.

SUMMARYCellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence supports age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profiled the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in 3 age groups. We found age-dependent and tissue-specific clock output changes. Aging reduced the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. Many genes gained rhythmicity in old tissues, reflecting an adaptive response. REGs were enriched for the hallmarks of aging, adding a new dimension to our understanding of aging. Differential gene expression analysis found that there were temporally distinct clusters of genes in tissue-specific manner. Increased daily gene expression variability is a common feature of aged tissues. This novel analysis extends the landscape of the understanding of aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.HIGHLIGHTS- Rhythmically expressed genes (REGs) in Young, but not Old mice, are enriched for the aging hallmarks across all tissues.- The numbers of REGs decline across all tissues with age implicating the circadian clock in altered homeostasis.- Age- and tissue-specific differentially expressed genes (DEGs) cluster at specific times of the day.- Increase in gene expression variability over a day is a common feature of aging tissues.

BackgroundThe risk of Alzheimer’s Disease (AD) is associated with muscle weakness, but the molecular basis of this association is unknown. Beyond motor function, skeletal muscle is a highly metabolic endocrine organ, and it crosstalks with other systems. Therefore, disruptions in skeletal muscle health may influence whole‐body homeostasis with AD progression. Accumulation of insoluble tau that forms neurofibrillary tangles (NFTs) is a hallmark of AD. Neurodegeneration could negatively impact muscle function; likewise, dysfunctional skeletal muscle can also deleteriously impact the environment of whole‐body processes, including tau pathogenesis. Therefore, measuring temporal changes in muscle function relative to insoluble tau accumulation would offer insight into whether skeletal muscle contributes to the progression of tau pathology.MethodsMale and female inducible muscle specific Bmal1 knockout (iMSBmal1KO) mice were used to model muscle weakness. Intracerebroventricular injections with adeno‐associated viral (AAV) vector encoding P301L human tau (n= 15) and yellow fluorescent protein (YFP) (n=18) were done at postnatal day 0. Grip strength, rotarod, and body composition were measured at 16 weeks. At 18 weeks, intraperitoneal injections were performed with either tamoxifen (n=8 tau, 11 YFP) or corn oil (n=7 tau, 7 YFP) to delete the core clock gene Bmal1 exclusively in skeletal muscle. Brains were harvested at 24 weeks. Soluble and insoluble tau were biochemically measured after a sarkosyl extraction protocol. Immunohistochemistry was performed. An additional cohort of wildtype C57BL/6 mice were intracerebroventricularly injected with AAV‐P301L human tau (n= 11) and the empty AAV construct (n= 10). Grip strength was measured at 10 and 12 weeks.ResultsGrip strength was reduced at 16 weeks in the mutant tau treated iMSBmal1KO mice, two weeks before induced muscle weakness, and 10 weeks before NFTs are reported in this tauopathy model. Insoluble tau was detected biochemically at 24 weeks. Grip strength was reduced in tau treated wildtype mice at 10 and 12 weeks.ConclusionsChanges in grip strength preceded NFT formation in this tauopathy model in both iMSBmal1 transgenic and wildtype mice. This suggests that a) muscle weakness may serve as a biomarker and b) that disrupted skeletal muscle health may be capable of contributing to tauopathy progression.

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