Exercise Preconditioning Preserves Cardiac Function and Enhances Cardiac Recovery Following Dobutamine Stimulation in Doxorubicin-Treated Rat Hearts.

Exercise preconditioning has been shown to protect against DOX-induced cardiac dysfunction when hearts are maintained under resting conditions. However, it is unclear whether this exercise-induced protective effect is maintained when the heart is challenged with the ß1-adrenergic receptor agonist dobutamine (DOB), which mimics acute exercise stress. Fischer 344 rats were randomly assigned to sedentary (SED) or voluntary wheel running (WR) groups for 10 weeks. At week 11, rats were treated with either 15 mg/kg DOX or saline (SAL). Five days later, ex vivo cardiac function was assessed using an isolating working heart model at baseline, during the infusion of 7.5 µg/kg/min DOB, and during recovery. DOB infusion significantly increased left ventricular developed pressure (LVDP), maximal (dP/dtmax) and minimal (dP/dtmin) rate of left ventricular pressure development, and heart rate in all groups (p<0.05). SED+DOX also showed a lower baseline and recovery LVDP than WR+DOX (83 ± 12 vs. 109 ± 6 mmHg baseline, 76 ± 11 vs. 100 ± 10 mmHg recovery, p<0.05). WR+DOX showed higher dP/dtmax and lower dP/dtmin when compared to SED+DOX during DOB infusion (7311 ± 1481 vs. 5167 ± 1436 mmHg/s and -4059 ± 1114 vs.-3158 ± 1176 mmHg/s, respectively). SED+DOX dP/dtmax was significantly lower during baseline and during recovery when compared to all other groups (p<0.05). These data suggest that exercise preconditioning preserved cardiac function after DOX exposure even when the heart is challenged with DOB, and it appeared to preserve the heart's ability to recover from this functional challenge.

BMPER is a marker of adipose progenitors and adipocytes and a positive modulator of adipogenesis.

Autocrine and paracrine signaling regulating adipogenesis in white adipose tissue remains largely unclear. Here we used single-cell RNA-sequencing (RNA-seq) and single nuclei RNA-sequencing (snRNA-seq) to identify markers of adipose progenitor cells (APCs) and adipogenic modulators in visceral adipose tissue (VAT) of humans and mice. Our study confirmed the presence of major cellular clusters in humans and mice and established important sex and diet-specific dissimilarities in cell proportions. Here we show that bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER) is a conserved marker for APCs and adipocytes in VAT in humans and mice. Further, BMPER is highly enriched in lineage negative stromal vascular cells and its expression is significantly higher in visceral compared to subcutaneous APCs in mice. BMPER expression and release peaked by day four post-differentiation in 3T3-L1 preadipocytes. We reveal that BMPER is required for adipogenesis both in 3T3-L1 preadipocytes and in mouse APCs. Together, this study identified BMPER as a positive modulator of adipogenesis.

Moderate Intensity Endurance and Resistance Exercise Attenuates Cachexia in Tumor-bearing Mice.

BACKGROUND/AIM: Cancer cachexia encompasses several deleterious physiological alterations associated with functional impairments, poor quality of life, and increased mortality. The aim of this study was to examine the effects of chronic moderate intensity exercise training on markers of cachexia. MATERIALS AND METHODS: Balb/c mice were randomly assigned to sedentary (SED) or exercise (EX) groups and EX mice were further randomly assigned to one of three exercise modalities (aerobic, resistance, combined). RESULTS: Cachexia was induced in SED animals inoculated with C26 cells, as evidenced by significant changes in numerous markers. All cachexia-related perturbations were significantly attenuated in EX versus SED animals. Systemic inflammation was significantly decreased in all EX groups, as evident by a normalization of spleen mass and plasma IL-6. CONCLUSION: Multiple moderate intensity exercise modalities can provide significant benefits in cachectic mice, and this may be due, at least in part, to decreased systemic inflammation.

The Effects of Exercise on White and Brown Adipose Tissue Cellularity, Metabolic Activity and Remodeling.

Emerging evidence suggests a significant functional role of adipose tissue in maintaining whole-body metabolic health. It is well established that obesity leads to compositional and morphological changes in adipose tissue that can contribute to the development of cardiometabolic disorders. Thus, the function and size of adipocytes as well as perfusion and inflammation can significantly impact health outcomes independent of body mass index. Lifestyle interventions such as exercise can improve metabolic homeostasis and reduce the risk for developing cardiometabolic disorders. Adipose tissue displays remarkable plasticity in response to external stimuli such as dietary intervention and exercise. Here we review systemic and local effects of exercise that modulate white and brown adipose tissue cellularity, metabolic function and remodeling in humans and animals.

Physical activity delays accumulation of immunosuppressive myeloid-derived suppressor cells.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are potent suppressors of immune function and may play a key role in the development and progression of metastatic cancers. Aerobic exercise has been shown to have anticancer effects, yet the mechanisms behind this protection are largely unknown. Therefore, we examined the effects of physical activity on MDSC accumulation and function. METHODS: Female BALB/c mice were assigned to one of two primary groups: sedentary tumor (SED+TUM) or wheel run tumor (WR+TUM). After 6 weeks of voluntary wheel running, all animals were randomly subdivided into 4 different timepoint groups; 16, 20, 24, and 28 days post-tumor injection. All mice were inoculated with 4T1 mammary carcinoma cells in the mammary fat pad and WR groups continued to run for the specified time post-injection. Spleen, blood, and tumor samples were analyzed using flow cytometry to assess proportions of MDSCs. RESULTS: Cells expressing MDSC biomarkers were detected in the spleen, blood, and tumor beginning at d16. However, since there was no evidence of immunosuppressive function until d28, we refer to them as immature myeloid cells (IMCs). Compared to SED+TUM, levels of IMCs in the spleen were significantly lower (p < 0.05) in WR+TUM at day 16 (33.0 ± 5.2%; 23.1 ± 10.2% of total cells, respectively) and day 20 (33.9 ± 8.1%; 24.3 ± 5.1% of total cells, respectively). Additionally, there were fewer circulating IMCs in WR+TUM at day 16 and MDSC levels were significantly lower (p < 0.05) in the tumor at day 28 in WR+TUM. Additionally, a non-significant 62% and 26% reduction in metastatic lung nodules was observed at days 24 and 28, respectively. At day 28, MDSCs harvested from SED+TUM significantly suppressed CD3+CD4+ T cell proliferation (3.2 ± 1.3 proliferation index) while proliferation in WR+TUM MDSC co-cultures (5.1 ± 1.7 proliferation index) was not different from controls. CONCLUSIONS: These findings suggest that physical activity may delay the accumulation of immunosuppressive MDSCs providing a broader window of opportunity for interventions with immunotherapies.