Biology subjects

Koch, L. G.

Publications and source records attributed to Koch, L. G..

4 recordsLinked to original sources

bioRxiv2024

Aerobic capacity and exercise mediate protection against hepatic steatosis via enhanced bile acid metabolism.

High cardiorespiratory fitness and exercise show evidence of altering bile acid (BA) metabolism and are known to protect or treat diet-induced hepatic steatosis, respectively. Here, we tested the hypothesis that high intrinsic aerobic capacity and exercise both increase hepatic BA synthesis measured by the incorporation of 2H2O. We also leveraged mice with inducible liver-specific deletion of Cyp7a1 (LCyp7a1KO), which encodes the rate-limiting enzyme for BA synthesis, to test if exercise-induced BA synthesis is critical for exercise to reduce hepatic steatosis. The synthesis of hepatic BA, cholesterol, and de novo lipogenesis was measured in rats bred for either high (HCR) vs. low (LCR) aerobic capacity consuming acute and chronic high-fat diets. HCR rats had increased synthesis of cholesterol and certain BA species in the liver compared to LCR rats. We also found that chronic exercise with voluntary wheel running (VWR) (4 weeks) increased newly synthesized BAs of specific species in male C57BL/6J mice compared to sedentary mice. Loss of Cyp7a1 resulted in fewer new BAs and increased liver triglycerides compared to controls after a 10-week high-fat diet. Additionally, exercise via VWR for 4 weeks effectively reduced hepatic triglycerides in the high-fat diet-fed control male and female mice as expected; however, exercise in LCyp7a1KO mice did not lower liver triglycerides in either sex. These results show that aerobic capacity and exercise increase hepatic BA metabolism, which may be critical for combatting hepatic steatosis. HighlightsO_LIRats with intrinsic high aerobic capacity have more significant reductions in de novo lipogenesis and increased cholesterol and bile acid synthesis on a high-fat diet compared to rats with low aerobic capacity. C_LIO_LIChronic exercise increases hepatic bile acid synthesis in mice. C_LIO_LILoss of Cyp7a1 blunts the capacity for exercise to increase bile acid synthesis and treat hepatic steatosis in male and female mice fed a high-fat diet. C_LI

physiology↗

bioRxiv2024

Organ specificity and commonality of epigenetic aging in low- and high-running capacity rats

BackgroundEpigenetic drift, which are gradual age-related changes in DNA methylation patterns, plays a significant role in aging and age-related diseases. However, the relationship between exercise, epigenetics, and aging and the molecular mechanisms underlying their interactions are poorly understood. The aim of this study was to investigate the relationship between cardiorespiratory fitness (CRF), epigenetic aging, and promoter methylation of individual genes across multiple organs in selectively bred low- and high-capacity runner (LCR and HCR) aged rats. MethodsIn this study, we performed reduced representation bisulfite sequencing (RRBS) on LCR and HCR aged rats, focusing on the hippocampus, heart, soleus muscle, and large intestine samples. We calculated various epigenetic indicators, including rat epigenetic clocks, global mean DNA methylation (GMM), mean methylation entropy (MME), and gene-specific promoter methylation. ResultsEpigenetic clocks, trained on available rat blood-derived RRBS data did not reflect differences in CRF between LCR and HCR rats across all four organs. However, we observed organ specific differences in GMM and MME between LCR and HCR rats. The direction of these differences was the opposite compared to the age-related changes in the rat blood suggesting that a high CRF may mitigate age-related epigenetic changes in an organ-specific manner. Notably the soleus muscle, exhibited the most pronounced differences in promoter methylation due to CRF. We also identified seven genes whose promoter methylation was consistently influenced by CRF in all four organs. Moreover, we found that age acceleration of the soleus muscle was significantly higher compared to the heart and the hippocampus, and significantly lower compared to the large intestine. Finally, we found that the age acceleration was not consistent across organs. ConclusionsOur data suggest that CRF associates with epigenetic aging in an organ-specific manner and regulates the promoter methylation of individual genes in an organ-specific and organ-common manner. Our findings provide important insights into the biology of aging and emphasize the need to validate rejuvenation strategies in the context of the organ-specific nature of epigenetic aging.

physiology↗

bioRxiv2024

Metformin treatment results in distinctive skeletal muscle mitochondrial remodeling in rats with different intrinsic aerobic capacities

The rationale for the use of metformin as a treatment to slow aging was largely based on data collected from metabolically unhealthy individuals. For healthspan extension metformin will also be used in periods of good health. To understand potential context specificity of metformin treatment on skeletal muscle, we used a rat model (HCR/LCR) with a divide in intrinsic aerobic capacity. Outcomes of metformin treatment differed based on baseline intrinsic mitochondrial function, oxidative capacity of the muscle (gastroc vs soleus), and the mitochondrial population (IMF vs SS). Metformin caused lower ADP-stimulated respiration in LCRs, with less of a change in HCRs. However, a washout of metformin resulted in an unexpected doubling of respiratory capacity in HCRs. These improvements in respiratory capacity were accompanied by mitochondrial remodeling that included increases in protein synthesis and changes in morphology. Our findings raise questions about whether the positive findings of metformin treatment are broadly applicable.

physiology↗

bioRxiv2018

Evolutionary origin of disease and complexity: A nonequilibrium thermodynamic solution

Our long-term goal was to develop realistic animal models of complex disease that are underwritten by fundamental principles. Along this path we noted a literature demonstrating that low exercise capacity is a stronger predictor of death relative to all other clinical conditions including diabetes and smoking. From this linkage we formulated the Energy Transfer Hypothesis (ETH): Variation in capacity for energy transfer is the central mechanistic determinant of the divide between disease and health. As an unbiased test of the ETH we reasoned that: divergent artificial selection of rats based on low and high intrinsic treadmill running capacity would yield contrasting models of capacity for energy transfer that also divide for disease risks. Thirty-five generations of selection produced Low Capacity Runners (LCR) and High Capacity Runners (HCR) that differ in running capacity by over 8-fold. Selection failed to disprove the ETH: disease risks segregate in the LCR, and the HCR demonstrate resistance to disease. For mechanistic explanation of the ETH we postulate that evolution, life, and thus disease follow the same entropic path of the other atoms and molecules of the universe. That is, 1) all systems tend towards Maximal Entropy Production, 2) entropy can temporarily decrease locally and form order such as life, 3) life developed with a genome as a path for coding for replication of energy metabolism units, and 4) evolution selects, in a constantly changing environment, for features that enhance lifes capacity for energy transfer. That is, Maximal Entropy Production is the driving force mediating evolution. Thus, for each species, consider that there is phenotypic variation for this capacity that underlies the divide between health and disease. One goal of this paper is to stimulate new cross-disciplinary tests of the ETH of disease.

evolutionary biology↗