Sex-specific skeletal muscle gene expression responses to exercise reveal novel direct mediators of insulin sensitivity change.
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2025-04
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Understanding how exercise improves whole-body insulin sensitivity (Si) involves complex molecular signaling. This study examines skeletal muscle gene expression changes related to Si, considering sex differences, exercise amount, and intensity to identify pharmacologic targets mimicking exercise benefits. Fifty-three participants from STRRIDE (Studies of Targeted Risk Reduction Interventions through Defined Exercise) I and II completed eight months of aerobic training. Gene expression was assessed via Affymetrix and Illumina technologies, and Si was measured using intravenous glucose tolerance tests. A novel discovery protocol integrating literature-derived and data-driven modeling identified causal pathways and direct transcriptional targets. In women, exercise amount primarily influenced transcription factor targets, which were generally inhibitory, while in men, exercise intensity drove activating targets. Common transcription factors included ATF1, CEBPA, BACH2, and STAT1. Si-related transcriptional targets included TACR3 and TMC7 for intensity-driven effects, and GRIN3B and EIF3B for amount-driven effects. Two key pathways mediating Si improvements were identified: estrogen signaling and protein kinase C (PKC) signaling, both converging on the epidermal growth factor receptor (EGFR) and other relevant targets. The molecular pathways underlying Si improvements varied by sex and exercise parameters, highlighting potential skeletal muscle-specific drug targets such as EGFR to replicate the metabolic benefits of exercise.
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Ma, Sisi, Monica J Hubal, Matthew C Morris, Leanna M Ross, Kim M Huffman, Christopher G Vann, Nadia Moore, Elizabeth R Hauser, et al. (2025). Sex-specific skeletal muscle gene expression responses to exercise reveal novel direct mediators of insulin sensitivity change. NAR molecular medicine, 2(2). p. ugaf010. 10.1093/narmme/ugaf010 Retrieved from https://hdl.handle.net/10161/33866.
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Scholars@Duke
Leanna Ross
Dr. Ross's research focuses on understanding the mechanisms by which exercise interventions elicit short- and long-term cardiometabolic health benefits. As cardiometabolic disease remains the leading cause of morbidity and mortality in the United States, the goal of her translational research is to enhance the development of evidence-based, precision exercise interventions that optimally prevent and treat disease.
Areas of Research Interest
Exercise dose-response and cardiometabolic health
Insulin action and glucose homeostasis
Legacy health benefits of exercise
Heterogeneity of response to exercise intervention
Precision lifestyle medicine
Epidemiology of physical activity and cardiorespiratory fitness
Elizabeth Rebecca Hauser
The incorporation of personalized medicine to all areas of human health represents a turning point for human genetics studies, a point at which the discoveries made have real implications for clinical medicine. It is important for students to gain experience in how human genetics studies are conducted and how results of those studies may be used. As a statistical geneticist and biostatistician my research interests are focused on developing and applying statistical methods to search for genes causing common human diseases. My research programs combine development and application of statistical methods for genetic studies, with a particular emphasis on understanding the joint effects of genes and environment.
These studies I work on cover diverse areas in biomedicine but are always collaborative, with the goal of bringing robust data science and statistical methods to the project. Collaborative studies include genetic and ‘omics studies of cardiovascular disease, health effects of air pollution, genetic analysis of adherence to an exercise program, genetic analysis in evaluating colon cancer risk, genetic analysis of suicide, and systems biology analysis of Gulf War Illness.
Keywords: human genetics, genetic association, gene mapping, genetic epidemiology, statistical genetics, biostatistics, cardiovascular disease, computational biology, diabetes, aging, colon cancer, colon polyps, kidney disease, Gulf War Illness, exercise behavior, suicide
Virginia Byers Kraus
Virginia Byers Kraus, MD, PhD, is the Mary Bernheim Distinguished Professor of Medicine, Professor of Orthopaedic Surgery, Professor of Pathology and a faculty member of the Duke Molecular Physiology Institute in the Duke University School of Medicine. She is a practicing Rheumatologist with over 30 years’ experience in translational musculoskeletal research focusing on osteoarthritis, the most common of all arthritides. She trained at Brown University (ScB 1979), Duke University (MD 1982, PhD 1993) and the Duke University School of Medicine (Residency in Internal Medicine and Fellowship in Rheumatology). Her career has focused on elucidating osteoarthritis pathogenesis and translational research into the discovery and validation of biomarkers for early osteoarthritis detection, prediction of progression, monitoring of disease status, and facilitation of therapeutic developments. She is co-PI of the Foundation for NIH Biomarkers Consortium Osteoarthritis project. Trained as a molecular biologist and a Rheumatologist, she endeavors to study disease from bedside to bench.
William Erle Kraus
My training, expertise and research interests range from human integrative physiology and genetics to animal exercise models to cell culture models of skeletal muscle adaptation to mechanical stretch. I am trained clinically as an internist and preventive cardiologist, with particular expertise in preventive cardiology and cardiac rehabilitation. My research training spans molecular biology and cell culture, molecular genetics, and integrative human exercise physiology and metabolism. I practice as a preventive cardiologist with a focus on cardiometabolic risk and exercise physiology for older athletes. My research space has both a basic wet laboratory component and a human integrative physiology one.
One focus of our work is an integrative physiologic examination of exercise effects in human subjects in clinical studies of exercise training in normal individuals, in individuals at risk of disease (such as pre-diabetes and metabolic syndrome; STRRIDE), and in individuals with disease (such as coronary heart disease, congestive heart failure and cancer).
A second focus of my research group is exploration of genetic determinates of disease risk in human subjects. We conduct studies of early onset cardiovascular disease (GENECARD; CATHGEN), congestive heart failure (HF-ACTION), peripheral arterial disease (AMNESTI), and metabolic syndrome. We are exploring analytic models of predicting disease risk using established and innovative statistical methodology.
A third focus of my group’s work is to understand the cellular signaling mechanisms underlying the normal adaptive responses of skeletal muscle to physiologic stimuli, such as occur in exercise conditioning, and to understand the abnormal maladaptive responses that occur in response to pathophysiologic stimuli, such as occur in congestive heart failure, aging and prolonged exposure to microgravity.
Recently we have begun to investigate interactions of genes and lifestyle interventions on cardiometabolic outcomes. We have experience with clinical lifestyle intervention studies, particularly the contributions of genetic variants to interventions responses. We call this Lifestyle Medicopharmacogenetics.
KEY WORDS:
exercise, skeletal muscle, energy metabolism, cell signaling, gene expression, cell stretch, heart failure, aging, spaceflight, human genetics, early onset cardiovascular disease, lifestyle medicine
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