With obesity and the metabolic syndrome being increasingly recognized as emerging major public health problems, "biomarkers for the progression of NIDDM (non-insulin dependent diabetes mellitus, or type-2 diabetes) are sorely needed, as are quantitative endpoints for exercise and diet interventions," according to Dustin S. Hittel of the Research Center for Genetic Medicine at Children's National Medical Center (CNMC), Washington, D.C.
Hittel said the results of a recent study "indicate the widespread and differential expression of metabolic, contractile and signal transduction proteins with training. We believe that comparative mRNA and proteomic profiling has provided us with a unique insight into the underlying metabolic crisis in chronically untrained muscle and clues as to how exercise reverses these effects."
Editors note: Hittel is speaking at the American Physiological Society's 2004 Intersociety Meeting, "The Integrative Biology of Exercise," Oct. 6-9 in Austin. Information about the meeting can be found at (http://www.the-aps.org/meetings/aps/austin/). A detailed program, including abstracts, for the entire meeting is available upon request to members of the media.
Arrangements for on-site interviews, or telephone interviews during the meeting can be arranged through APS from Mayer Resnick (cell: 301-332-4402, mresnick@the-aps.org) or Stacy Brooks 301-634-7253 (sbrooks@the-aps.org). From Oct. 6 (2 p.m.) – Oct. 9, the onsite phone number in Austin is 512-482-8000, room 602, or 512-682-2950 direct.
STRRIDE study hints at skeletal muscle role in CVD risk improvement
Using subjects from the Studies of Targeted Risk Reduction Interventions through Defined Exercise (STRRIDE), Hittel and others "described the molecular basis for the improvement in several CVD risk factors associated with the metabolic syndrome and the importance of skeletal muscle in governing these changes."
The researchers also included William E. Kraus (Center for Living Lab, Duke University Medical Center), Joseph A. Houmard (Human Performance Laboratory and Diabetes/Obesity Center, East Carolina University) and Eric P. Hoffman (also of CNMC).
In the genomics area, according to Hittel, "we found coordinated up-regulation of key metabolic enzymes with aerobic training in metabolic syndrome aspartate aminotransferase 1, lactate dehydrogenase B and pyruvate dehydrogenase alpha 1 subunit. All were also quickly down-regulated by detraining, although the induction wasn't an acute response to activity." Protein and enzymatic assays were used to validate mRNA induction with aerobic training and loss with de-training (96 hours to two weeks) in 10 male and 10 female STRRIDE subjects.
"We propose that training coordinately increases the levels of aspartate aminotransferase 1, lactate dehydrogenase B and pyruvate dehydrogenase alpha 1 subunit, increasing glucose metabolism in muscle by liberating pyruvate for oxidative metabolism and therefore limiting lactate efflux," Hittel said. These biochemical adaptations complement existing molecular models for improved glucose tolerance with exercise intervention in pre-diabetic individuals, he noted.
On the proteomics side, the researchers analyzed gene expression and protein profiles from muscle of lean and obese and morbidly obese individuals. "This combination of genomic and proteomic techniques may help determine the effects of aerobic exercise and weight gain on muscle gene and protein expression patterns," Hittel said.
They found that adenylate kinase 1 (AK1), an important enzyme in regulation of cellular energy metabolism, particularly skeletal muscle, was highly expressed in obese and morbidly obese women relative to lean control subjects. Total muscle AK1 activity also increased 1.9-fold in obese and 2-fold in morbidly obese women. "Surprisingly," Hittel noted, "total activity of creatine kinase (CK), which also regulates energy metabolism in skeletal muscle, increased (a significant) 30% in obese women but not in morbidly obese women.
"We propose that the increased activities of AK1, CK reflect a compensatory change in energy metabolism to counter a progressive decrease in mitochondrial function in skeletal muscle of increasingly obese women. We feel that this discovery provides new insights into the primary deficits in muscle metabolisms which underlie the progression of obesity-related diseases," Hittel said.
In conclusion Hittel said, "we propose that changes in glucose metabolism which occur in aerobic exercise trained skeletal muscle are also responsible for the cardiovascular benefits of habitual exercise in individuals with impaired glucose tolerance."
The Austin exercise meeting is cosponsored by APS, the American College of Sports Medicine and the Canadian Society for Exercise Physiology. Additional support through unrestricted educational grants came from: the National Aeronautics and Space Administration (NASA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMSD), Gatorade Sports Sciences Institute, Pfizer Inc. and the U.S. Army Research Institute of Environmental Medicine (USARIEM).
The American Physiological Society was founded in 1887 to foster basic and applied bioscience. The Bethesda, Maryland-based society has more than 10,000 members and publishes 14 peer-reviewed journals containing almost 4,000 articles annually.
APS provides a wide range of research, educational and career support and programming to further the contributions of physiology to understanding the mechanisms of diseased and healthy states. In May, APS received the Presidential Award for Excellence in Science, Mathematics and Engineering Mentoring (PAESMEM).