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The study of the molecular basis of exercise adaptations in the field of exercise physiology is relatively new, as evidenced by the surge in articles citing molecular techniques over the last decade. This focus on molecular indicators is not surprising given the efforts to improve upon preventative healthcare and reduce healthcare cost burden in our country. The ability to exploit molecular indicators of exercise effectiveness as well as discover novel therapeutic options are clear advantages to studying molecular exercise physiology that could impact healthcare. In the studies described here, we used an integrative approach, building from a molecular basis to mice to human subjects, to develop a more comprehensive understanding of the molecular mechanisms mediating the effects of exercise. To study the effects of exercise on a physiological systems-wide level, we used microarray technology to characterize global upregulation and downregulation of genes in response to walking exercise in rat cartilage. We found temporal gene expression changes over 15 days of exercise. The networks of genes affected were responsible for directing extracellular matrix; cell metabolism; cytoskeleton; cell signaling, growth, and differentiation; and inflammatory pathways. It was evident from this study that integration of multiple physiological systems occurs in response to an exercise stimulus.We then aimed to isolate and study selected systems using molecular and physiological techniques. The objective of one particular study was to determine the role of exercise as an integrator of bone and muscle health. One of the genes that was observed during the microarray analysis to be upregulated by exercise by more than 1.5 fold was follistatin-like3 (FSTL3). FSTL3 belongs to the follistatin family of molecules which also includes follistatin (FST). Previous studies showed that FSTL3 is required for exercise driven bone formation. This protein also binds and inhibits myostatin, an inhibitor of muscle growth and strength, thus indicating a role for FSTL3 in hypertrophy and force generation. Using muscle contractility assays and genetic knockout mouse models, it was determined that walking exercise, while sufficient for bone growth, was not a potent enough stimulus for improvements in muscle hypertrophy and force generation.The follistatin family of proteins have been shown to be involved in cardiac health, thus we aimed to determine the role of follistatin 288 (FST288), a genetic knockout model for follistatin, in the heart with and without exercise and in response to pressure overload induced by transverse aortic constriction (TAC). We found that knockout of the circulating follistatin mediator, FST315, resulted in reduced hypertrophy in response to TAC, indicating that this molecule likely contributes to the generation of pathological hypertrophy in heart failure. Finally, we aimed to determine the translational potential of our FSTL3 studies in humans. Subjects were exposed to low intensity walking, high intensity walking, or a neuromuscular training program. Bone density, muscular strength, and serum levels of mediators in the follistatin/myostatin system were measured. It was concluded that walking was an insufficient stimulus for increasing FSTL3 to affect bone mass in humans, and that FSTL3 was not found to be a suitable biomarker for BMD. However, some gains in muscular strength were observed in previously sedentary patients.These studies show the importance of integration of multiple indicators (molecular, clinical, biochemical) in the study of the physiology of exercise, and they advance a growing field of knowledge. Future mechanistic studies of exercise will increase fundamental understanding that could be exploited to improve health by paving a path for biomarker discovery, developing methods for quantitation of exercise effectiveness, and advancing the possibility of personalized exercise prescriptions and novel therapeutics. |
