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Regular exercise promotes whole-body health and prevents disease, yet the underlying molecular mechanisms throughout a whole organism are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome, and immunome in whole blood, plasma, and 18 solid tissues in Rattus norvegicus over 8 weeks of endurance exercise training. The resulting data compendium encompasses 9466 assays across 19 tissues, 25 molecular platforms, and 4 training time points in young adult male and female rats. We identified thousands of shared and tissue- and sex- specific molecular alterations. Temporal multi-omic and multi-tissue analyses demonstrated distinct patterns of tissue remodeling, with widespread regulation of immune, metabolism, heat shock stress response, and mitochondrial pathways. These patterns provide biological insights into the adaptive responses to endurance training over time. For example, exercise training induced heart remodeling via altered activity of the Mef2 family of transcription factors and tyrosine kinases. Translational analyses revealed changes that are consistent with human endurance training data and negatively correlated with disease, including increased phospholipids and decreased triacylglycerols in the liver. Sex differences in training adaptation were widespread, including those in the brain, adrenal gland, lung, and adipose tissue. Integrative analyses generated novel hypotheses of disease relevance, including candidate mechanisms that link training adaptation to non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health, and tissue injury and recovery. The data and analysis results presented in this study will serve as valuable resources for the broader community and will be provided in an easily accessible public repository (https://motrpac-data.org/).

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Recent studies demonstrate that adaptations to white adipose tissue (WAT) are important components of the beneficial effects of exercise training on metabolic health. Exercise training favorably alters the phenotype of subcutaneous inguinal WAT (iWAT) in male mice, including decreasing fat mass, improving mitochondrial function, inducing beiging, and stimulating the secretion of adipokines. In this study, we find that despite performing more voluntary wheel running compared with males, these adaptations do not occur in the iWAT of female mice. Consistent with sex-specific adaptations, we report that mRNA expression of androgen receptor coactivators is upregulated in iWAT from trained male mice and that testosterone treatment of primary adipocytes derived from the iWAT of male, but not female mice, phenocopies exercise-induced metabolic adaptations. Sex specificity also occurs in the secretome profile, as we identify cysteine-rich secretory protein 1 (Crisp1) as a novel adipokine that is only secreted from male iWAT in response to exercise. Crisp1 expression is upregulated by testosterone and functions to increase glucose and fatty acid uptake. Our finding that adaptations to iWAT with exercise training are dramatically greater in male mice has potential clinical implications for understanding the different metabolic response to exercise training in males and females and demonstrates the importance of investigating both sexes in studies of adipose tissue biology.

Preclinical studies reveal maternal exercise as a promising intervention to reduce the transmission of multi-generational metabolic dysfunction caused by maternal obesity. The benefits of maternal exercise on offspring health may arise from multiple factors and have recently been shown to involve DNA demethylation of critical hepatic genes leading to enhanced glucose metabolism in offspring. Histone modification is another epigenetic regulator, yet the effects of maternal obesity and exercise on histone methylation in offspring are not known. Here, we find that maternal high fat diet (HFD; 60% kcal from fat) induced dysregulation of offspring liver glucose metabolism in C57BL/6 mice through mechanism involving increased reactive oxygen species, WD repeat-containing 82 (WDR82) carbonylation, and inactivation of H3K4 methyltransferase leading to decreased H3K4me3 at the promoters of glucose metabolic genes. Remarkably, the entire signal was restored if the HFD-fed dams had exercised during pregnancy. WDR82 overexpression in hepatoblasts mimicked the effects of maternal exercise on H3K4me3 levels. Placental superoxide dismutase 3 (SOD3), but not antioxidant treatment with N-acetylcysteine was necessary for the regulation of H3K4me3, gene expression and glucose metabolism. Maternal exercise regulates a multi-component epigenetic system in fetal liver resulting in the transmission of the benefits of exercise to offspring.

Background: Periprosthetic infections remain a major challenge for breast reconstruction. Local antibiotic delivery systems, such as antibiotic beads and spacers, have been widely used within other surgical fields, but their use within plastic surgery remains scarce. In this study, we demonstrate the use of antibiotic-impregnated polymethylmethacrylate (PMMA) plates for infection prophylaxis in tissue expander (TE)-based breast reconstruction. Methods: A retrospective review of patients who underwent immediate breast reconstruction with prepectoral TEs over the span of 5 years performed by two surgeons was completed, revealing a total of 447 patients. Data pertaining to patient demographics, operative details, and postoperative outcomes were recorded. Fifty patients underwent TE reconstruction with the addition of a PMMA plate (Stryker, Kalamazoo, Michigan) impregnated with tobramycin and vancomycin. Antibiotic plates were removed at the time of TE-to-implant exchange. Patient-matching analysis was performed using the 397 patients without PMMA plates to generate a 50-patient nonintervention cohort for statistical analysis. Results: The intervention cohort (n = 50) and 1:1 patient-matched nonintervention cohort (n = 50) demonstrated no statistically significant differences in patient demographics or operative characteristics other than PMMA plate placement. The rate of operative periprosthetic infection was 4% in the intervention group and 14% in the nonintervention group (P = 0.047). The rate of TE explantation was also reduced in the intervention group (6% versus 18%; P = 0.036). Follow-up averaged 9.1 and 8.9 months for the intervention and nonintervention groups, respectively (P = 0.255). Conclusion: Local antibiotic delivery using antibiotic-impregnated PMMA plates can be safely and effectively used for infection prevention with TE-based breast reconstruction.

Recent studies demonstrate that adaptations to white adipose tissue are important components of the beneficial effects of exercise training on metabolic health. Exercise training favorably alters the phenotype of subcutaneous inguinal white adipose tissue (iWAT) in male mice including decreasing fat mass, improving mitochondrial function, inducing beiging and stimulating the secretion of adipokines. Here, we find that despite performing more voluntary wheel running compared to males, these adaptations do not occur in the iWAT of female mice. Consistent with sex-specific adaptations, we report that mRNA expression of androgen receptor co-activators are upregulated in iWAT from trained male mice, and that testosterone treatment of primary adipocytes derived from the iWAT of male, but not female mice, phenocopies exercise-induced metabolic adaptations. Sex-specificity also occurs in the secretome profile, as we identify Cysteine Rich Secretory Protein 1(<i>Crisp1</i>) as a novel adipokine that is only secreted from male iWAT in response to exercise. <i>Crisp1</i> expression is upregulated by testosterone and functions to increase glucose and fatty acid uptake. Our finding that adaptations to iWAT with exercise training are dramatically greater in male mice has potential clinical implications for understanding the different metabolic response to exercise training in males and females, and demonstrates the importance of investigating both sexes in studies of adipose tissue biology.

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