Early Onset Physical Inactivity and Metabolic Dysfunction in Tumor-bearing Mice Is Associated with Accelerated Cachexia

Currently our society is faced with the challenge of understanding the biological basis for the epidemics of obesity and many chronic diseases, including Type 2 diabetes. Physical inactivity increases the relative risk of coronary artery disease by 45%, stroke by 60%, hypertension by 30%, and osteoporosis by 59%. Moreover, physical inactivity is cited as an actual cause of chronic disease by the US Centers of Disease Control. Physical activity was obligatory for survival for the Homo genus for hundreds of thousands of years. This review will present evidence that suggests that metabolic pathways selected during the evolution of the human genome are inevitably linked to physical activity. Furthermore, as with many other environmental interactions, cycles of physical activity and inactivity interact with genes resulting in a functional outcome appropriate for the environment. However, as humans are less physically active, there is a maladaptive response that leads to metabolic dysfunction and many chronic diseases. How and why these interactions occur are fundamental questions in biology. Finally, a perspective to future research in physical inactivity-gene interaction is presented. This information is necessary to provide the molecular evidence required to further promote the primary prevention of chronic diseases through physical activity, identify those molecules that will allow early disease detection, and provide society with the molecular information needed to counter the current strategy of adding physical inactivity into our lives.

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The Effects of Early-Onset Pre-Eclampsia on Placental Creatine Metabolism in the Third Trimester

International Journal of Molecular Sciences ◽

10.3390/ijms21030806 ◽

2020 ◽

Vol 21 (3) ◽

pp. 806 ◽

Cited By ~ 1

Author(s):

Stacey J. Ellery ◽

Padma Murthi ◽

Paul A. Della Gatta ◽

Anthony K. May ◽

Miranda L. Davies-Tuck ◽

...

Keyword(s):

Mrna Expression ◽

Early Onset ◽

Energy Homeostasis ◽

Metabolic Dysfunction ◽

Third Trimester ◽

Creatine Transporter ◽

Protein Levels ◽

Total Creatine ◽

Spatio Temporal ◽

Creatine Metabolism

Creatine is a metabolite important for cellular energy homeostasis as it provides spatio-temporal adenosine triphosphate (ATP) buffering for cells with fluctuating energy demands. Here, we examined whether placental creatine metabolism was altered in cases of early-onset pre-eclampsia (PE), a condition known to cause placental metabolic dysfunction. We studied third trimester human placentae collected between 27–40 weeks’ gestation from women with early-onset PE (n = 20) and gestation-matched normotensive control pregnancies (n = 20). Placental total creatine and creatine precursor guanidinoacetate (GAA) content were measured. mRNA expression of the creatine synthesizing enzymes arginine:glycine aminotransferase (GATM) and guanidinoacetate methyltransferase (GAMT), the creatine transporter (SLC6A8), and the creatine kinases (mitochondrial CKMT1A & cytosolic BBCK) was assessed. Placental protein levels of arginine:glycine aminotransferase (AGAT), GAMT, CKMT1A and BBCK were also determined. Key findings; total creatine content of PE placentae was 38% higher than controls (p < 0.01). mRNA expression of GATM (p < 0.001), GAMT (p < 0.001), SLC6A8 (p = 0.021) and BBCK (p < 0.001) was also elevated in PE placentae. No differences in GAA content, nor protein levels of AGAT, GAMT, BBCK or CKMT1A were observed between cohorts. Advancing gestation and birth weight were associated with a down-regulation in placental GATM mRNA expression, and a reduction in GAA content, in control placentae. These relationships were absent in PE cases. Our results suggest PE placentae may have an ongoing reliance on the creatine kinase circuit for maintenance of cellular energetics with increased total creatine content and transcriptional changes to creatine synthesizing enzymes and the creatine transporter. Understanding the functional consequences of these changes warrants further investigation.

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M13. Identifying Youths at Risk for Antipsychotic-Induced Weight Gain and Metabolic Dysfunction in the Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)

Schizophrenia Bulletin ◽

10.1093/schbul/sbx022.012 ◽

2017 ◽

Vol 43 (suppl_1) ◽

pp. S215-S216

Author(s):

Jerome Taylor ◽

Ewgeni Jakubovski ◽

Daniel Gabriel ◽

Michael Bloch

Keyword(s):

At Risk ◽

Weight Gain ◽

Early Onset ◽

Metabolic Dysfunction ◽

Schizophrenia Spectrum Disorders ◽

Early Onset Schizophrenia ◽

Schizophrenia Spectrum ◽

Spectrum Disorders

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Metabolic dysfunction and early‐onset colorectal cancer – how macrophages build the bridge

Cancer Medicine ◽

10.1002/cam4.3315 ◽

2020 ◽

Vol 9 (18) ◽

pp. 6679-6693

Author(s):

Katharina M. Scheurlen ◽

Adrian T. Billeter ◽

Stephen J. O'Brien ◽

Susan Galandiuk

Keyword(s):

Colorectal Cancer ◽

Early Onset ◽

Metabolic Dysfunction ◽

Early Onset Colorectal Cancer

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Identifying pathways to early‐onset metabolic dysfunction, insulin resistance and inflammation in young adult inpatients with emerging affective and major mood disorders

Early Intervention in Psychiatry ◽

10.1111/eip.13260 ◽

2021 ◽

Author(s):

Ashleigh M. Tickell ◽

Cathrin Rohleder ◽

Nicholas Ho ◽

Catherine McHugh ◽

Graham Jones ◽

...

Keyword(s):

Insulin Resistance ◽

Young Adult ◽

Mood Disorders ◽

Early Onset ◽

Metabolic Dysfunction

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Comparative Transcriptomic Profiling of Organs Associated With Metabolic Dysfunction in Cancer-Induced Cachexia

Current Developments in Nutrition ◽

10.1093/cdn/nzab041_016 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 501-501

Author(s):

Ji-Won Heo ◽

Sung-Eun Kim

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Energy Metabolism ◽

Cancer Cachexia ◽

Gene Set Enrichment Analysis ◽

Glutamine Metabolism ◽

Metabolic Dysfunction ◽

Network Analyses ◽

Tumor Bearing

Abstract Objectives Approximately 50–80% of cancer patients suffer from cachexia represented by weight loss mainly due to loss of skeletal muscle. Cancer-induced cachexia is a complex metabolic syndrome associated with not only systemic inflammation but also perturbations to energy metabolism. In this study, we profiled gene expression patterns of different organs in CT-26 tumor bearing mice in order to understand metabolic dysfunction in cancer cachexia. Methods The transcriptomic profiles of skeletal muscle, adipose tissue, and liver of CT26-tumor bearing mice were generated using SurePrint G3 Mouse Gene Expression 8 × 60 K v2 (Agilent, Inc.). Functional and network analyses were performed using Gene Set Enrichment Analysis and Ingenuity Pathway Analysis (QIAGEN). Results We identified 299, 508, and 1,311 genes differentially regulated in skeletal muscle, adipose tissue, and liver, respectively. In the skeletal muscle, lipid biosynthetic process and mitochondrial electron transport were negatively regulated and network involved in glutamine metabolism was up-regulated. In adipose tissue, tricarboxylic acid cycle was down-regulated and lipid metabolism was associated with several genes including Thrsp, Plvap, and Sphk1. In the liver, regulation of gluconeogenesis was down-regulated, while production of lactic acid and uptake of D-glucose were related with H6pd and Pkm whose expression was up-regulated during cancer cachexia. Furthermore, the top network matched by genes commonly up-regulated in all organs included Bcl3, Csf2rb, Fcgr2a, and Lilrb3, which are known to be associated with inflammation and muscle wasting. Conclusions Our data suggest that skeletal muscle, adipose tissue, and liver present distinct gene expression profiles associated with inflammation and energy metabolism and several genes up-regulated in all organs might be candidate biomarkers for the prevention and early detection of cancer cachexia. Funding Sources This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education.

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Pre-Clinical Rodent Models of Physical Inactivity-Induced Muscle Insulin Resistance: Challenges and Solutions

Journal of Applied Physiology ◽

10.1152/japplphysiol.00954.2020 ◽

2020 ◽

Author(s):

Paul T. Reidy ◽

Jackie M. Monning ◽

Carrie E. Pickering ◽

Katsuhiko Funai ◽

Micah J. Drummond

Keyword(s):

Insulin Resistance ◽

Physical Inactivity ◽

Lifestyle Modification ◽

Academic Research ◽

Metabolic Dysfunction ◽

Rodent Models ◽

Lifestyle Modifications ◽

Initial Development ◽

Muscle Disuse ◽

Health Complications

The burgeoning rise of health complications emanating from metabolic disease presents an alarming issue with mounting costs for health care and a reduced quality of life. There exists a pressing need for more complete understanding of mechanisms behind the development and progression of metabolic dysfunction. Since lifestyle modifications such as poor diet and lack of physical activity are primary catalysts of metabolic dysfunction, rodent models have been formed to explore mechanisms behind these issues. Particularly, the use of high-fat diet has been pervasive and has been an instrumental model to gain insight into mechanisms underlying diet-induced insulin resistance (IR). However, physical inactivity (and to some extent muscle disuse) is an often overlooked and much less frequently studied lifestyle modification, which some have contended is the primary contributor in the initial development of muscle IR. In this mini-review we highlight some of the key differences between diet- and physical inactivity-induced development of muscle IR and propose reasons for the sparse volume of academic research into physical inactivity-induced IR including infrequent use of clearly translatable rodent physical inactivity models.

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