Cellular and Molecular Exercise Physiology: A Historical Perspective for the Discovery of Mechanisms Contributing to Skeletal Muscle Adaptation

Cellular and molecular exercise physiology is the study of the underlying regulatory mechanisms that underpin physiological adaptation to exercise. In this historical perspective, I explained how the field emerged following advancements in technology within the molecular biology field in general and as a result of some exciting forward thinking by the leading exercise biochemists of the time. I also discuss the important advancements in elucidating the mechanisms underlying physiological adaptation to exercise using genetic knockout, overexpression and compensatory hypertrophy models in animals that subsequently enabled the study and translation of key mechanisms that underpin human exercise adaptation. This historical perspective also helps decipher the important studies that pioneered the investigation of the cellular signaling networks controlling gene expression in response to acute and chronic exercise, the role of satellite cells in repair of skeletal muscle after exercise and finally how the important topic of exercise genetics/genomics emerged within the cellular and molecular exercise physiology field. Finally, the manuscript identifies that the integration of epigenetics and proteomics to compliment current genome-wide approaches (profiling of heritable genetic variants and gene expression) are likely to play an important role in uncovering the cellular and molecular regulation of exercise adaptation into the next generation.

In this chapter, we define molecular exercise physiology and provide a history of the evolution of molecular exercise physiology as a scientific discipline. We describe how the origins of molecular exercise physiology emerged from early pioneering research undertaken by exercise biochemists and rapid advances in molecular biology techniques. The chapter includes a narrative from Professor Frank Booth, who was one of the first researchers to apply molecular biology techniques to exercise physiology, as well as a narrative from exercise genomics pioneer, Professor Claude Bouchard. In this chapter, we also outline the importance of various experimental models that have enabled important discoveries in human molecular exercise physiology. We also highlight some of the landmark research contributing to this discipline. Finally, we discuss the advancement in integrative ‘OMICs’ and how this type of ‘discovery’ analyses, coupled with experimental models to confirm these discoveries, is likely to advance molecular exercise physiology as a field into the future. Finally, we provide a fundamental overview of the chapter structure for the rest of the book.

Chapter Ten - Exercise and DNA methylation in skeletal muscle

Exercise physiology has evolved as a main area of investigation, in which the central goal is to better understand how the physiological systems respond to an acute bout of exercise and how these systems adapt to different types of exercise training. For many years and until now, exercise physiology field have been grounded in the fundamentals of biology and human physiology. However, during the last century, scientific knowledge has changed our understanding of biological sciences, allowing the integration of different areas, and increasing the focus on many sub-areas like cellular and molecular investigation. The development of new experimental techniques in the last years provided detailed information about cellstructure and function and, as a result, we could better understand not only the human body physiology, but also many diseases and their pathophysiology. Therefore, this present review intends to discuss more about cellular and molecular exercise physiology area, focusing on historical and methodological approaches, and highlighting the future perspectives for scientific knowledge and their practical application in health and exercise.

Exercise physiology has evolved as a main area of investigation, in which the central goal is to better understand how the physiological systems respond to an acute bout of exercise and how these systems adapt to different types of exercise training. For many years and until now, exercise physiology field have been grounded in the fundamentals of biology and human physiology. However, during the last century, scientific knowledge has changed our understanding of biological sciences, allowing the integration of different areas, and increasing the focus on many sub-areas like cellular and molecular investigation. The development of new experimental techniques in the last years provided detailed information about cellstructure and function and, as a result, we could better understand not only the human body physiology, but also many diseases and their pathophysiology. Therefore, this present review intends to discuss more about cellular and molecular exercise physiology area, focusing on historical and methodological approaches, and highlighting the future perspectives for scientific knowledge and their practical application in health and exercise.

MEAD, JERE, TAMOTSU TAKISHIMA, AND DAVID LEITH. Stress distribution in lungs: a model of pulmonary elasticity. J. Appl. Physiol. 28(5) : 596-608. 1970.Although lungs are exposed to transpulmonary pressure, the air spaces within are distended solely by forces applied from surrounding tissues. By relating these forces to the areas on which they operate, we derive the effective pressure distending air spaces. In uniformly expanded lungs this pressure probably approximates transpulmonary pressure. In nonuniformly expanded lungs the effective distending pressure differs from transpulmonary pressure, and in the appropriate sign to reduce the nonuniformity. This interdependence of air-space distention bears on a number of aspects of pulmonary function, including the size of air spaces which may be expanded from the gas-free state, the static and dynamic stability of air spaces, the dryness of air spaces, the forces distending airways and blood vessels within lungs, and the distribution of pulmonary edema. The principal function of the mechanical interdependence would appear to be to support uniform expansion of air spaces. The principal functional risk that it entails is increase in capillary transmural pressure in regions which become subjected to abnormally high outward-acting stress.

Molecular exercise physiology is the study of exercise physiology using molecular biology methods. The development of differentiated cell types is regulated by transcription factors like the muscle-making MyoD that specifies cell type, while others regulate the development of muscle, tendons, and bones. Maternal nutrition and exercise commonly affect embryonic development through epigenetic mechanisms. Adaptation to exercise involves sensor proteins detecting exercise-related signals, the processing of signals by signalling proteins and networks, and the regulation of the actual adaptations by effector proteins. Many sport- and exercise-related traits depend on both common and rare DNA sequence variations, including the muscle mass-increasing myostatin (GDF8) loss-of-function and the haematocrit-increasing EPOR gain-of-function mutations. Additionally, common DNA sequence variations contribute to the inherited variability of development, body height, strength, and endurance. Finally, in addition to ethical concerns, current genetic performance tests only explain a fraction of the variation of sport and exercise-related traits.

Skeletal muscle reaction to exercise is an essential are of research due to its ongoing prevalence in disease research and general health. It is well documented that under exercise conditions, biogenesis and autophagy increase. One main component of this pathway are lysosomes, the essential cellular clearance machine. Statistical analyses used to analyze these data have been sustained over the years. The objective of this systematic review is to compare and contrast the different methods used for analyzing data in molecular exercise physiology. Upon investigating the research papers the majority of the papers used either a t-test or an ANOVA as their primary statistical analyses, used 41% and 64% of the time, respectively. All other statistical tests were used a maximum of 9% of the time. Another trend that was evident was the increased utilization of post hoc tests in the more recent papers compared to earlier papers. This could provide interesting evidence into the credibility of the results reported and provide more insight into the research in molecular exercise physiology.

Faculty Opinions recommendation of Cellular and Molecular Exercise Physiology: Historical Perspective for the Discovery of Mechanisms Contributing to Skeletal Muscle Adaptation.

Effects of a mitochondria-targeted antioxidant (MitoQ) in murine experimental acute pancreatitis

Bakhtyar Tartibian1, Behzad Hajizadeh Maleki1, Asghar Abbasi2, Mehdi Eghbali3, Siamak Asri-Rezaei3 and Hinnak Northoff4 1Department of Cellular and Molecular Exercise Physiology, Faculty of Physical Education and Sport Science, Urmia University, Urmia 2Institute of Sport Science, University of Tuebingen 3Department of Clinical Science, Faculty of Veterinary Medicine, Urmia University, Urmia 4Institute of Clinical and Experimental Transfusion Medicine (IKET), University of Tuebingen 1,3Iran 2,4Germany

Estimation of equivalent pore radii of pulmonary capillary and alveolar membranes

Morphological basis of alveolar-capillary gas exchange.

Satellite cells are myogenic cells that play a critical role in skeletal muscle repair. They serve as stem cells for muscles, remaining dormant in healthy muscle but activating upon injury resulting in increased proliferation and differentiation into myoblasts. Another key aspect of muscle regeneration is reestablishing vascular supply, but the role of satellite cells in this process is not well established though they are known to produce a number of potential paracrine signals. Thus we hypothesized that satellite cells promote vascular growth through paracrine signaling induced by activation following muscle injury or ischemic damage from diseases such as peripheral artery disease. Using a murine model of hind limb ischemia, we showed that satellite cells increased 3.4 fold (p<0.01) in response to ischemia. To determine if satellite cells produce paracrine factors, we used a co-culture system for migration and proliferation. Satellite cells freshly isolated from the ischemic limb led to a 3.5 fold increase in smooth muscle migration (p<0.0001) and a 1.3 fold increase (p<0.01) in smooth muscle proliferation. Additionally, cultured satellite cells increased endothelial cell migration 2.8 fold. These results demonstrate the satellite cells produce paracrine factors which can drive both smooth muscle and endothelial cell migration and proliferation which are required for the development of collateral vessels. To test the potential therapeutic capability of satellite cells, alginate encapsulated satellite cells were delivered in the hind limb ischemic model. Using a whole animal in vivo imager to track luciferase expression of the cells, we found the encapsulated cells were viable for up to 2 weeks. The mice that received satellite cells also had significantly increased perfusion (28%, p<0.05) at 2 weeks as measured by Laser Doppler imaging. In conclusion our studies have shown that satellite cells increase in response to ischemia, produce paracrine factors that increase vascular cell migration in vitro, and lead to functional increases in perfusion in vivo. We believe these results demonstrate the critical role satellite cells play in collateral vessel formation and may be a potential new therapeutic approach for treating peripheral artery disease.

Satellite cells are myogenic cells that play a critical role in skeletal muscle repair. In healthy muscle they are maintained in a quiescent state but upon injury to the muscle they activate resulting in increased proliferation. While many of the activated satellite cells differentiate into myoblasts which fuse to repair the muscle, some return to the quiescent state to serve as a “stem cell” population. However, another key aspect of muscle regeneration is reestablishing vascular supply, yet the role of satellite cells in this process is not well established. Satellite cells have been shown to produce several proteins that have the potential to act as paracrine signals. Thus, we hypothesized that satellite cells promote vascular growth through paracrine signaling induced by activation following muscle injury or ischemic damage from diseases such as peripheral artery disease. The model of collateral growth used in this study was a murine model of hind limb ischemia in which the femoral artery and vein are ligated and excised. Using this model, we showed ischemic muscle damage increased satellite cell numbers 3.4 fold (p<0.01) as measured by isolating cells from the hind limb muscles using magnetic bead sorting. To determine if satellite cells produce paracrine factors, we used a modified Boyden chamber co‐culture system for migration where satellite cells served as the chemoattractant and proliferation where satellite cells were the growth stimuli. We found that satellite cells freshly isolated from the ischemic limb led to a 3.5 fold increase in smooth muscle cell migration (p<0.0001) and a 1.3 fold increase (p<0.01) in smooth muscle cell proliferation. Additionally, cultured satellite cells increased endothelial cell migration 1.9 fold and proliferation 1.3 fold. Both smooth muscle cell and endothelial cell migration and proliferation are required for the development of collateral vessels, and these results demonstrate that satellite cells produce paracrine factors that increase both of these critical processes. To test the potential therapeutic capability of satellite cells in vivo, alginate encapsulated satellite cells were delivered in the hind limb at the time of the ischemia procedure. Alginate encapsulation has been previously shown to increase the cell retention and viability of other cell types, and using a whole animal in vivo imager to track luciferase expression of the cells, we found the encapsulated cells were viable for up to 2 weeks. The satellite cells also improved the recovery with the mice that received satellite cells having significantly increased perfusion over the mice that received empty capsules at 2 weeks post‐surgery as measured by Laser Doppler imaging (perfusion ratio of 0.87 ± 0.04 (cells) vs 0.68 ± 0.07 (empty capsules), p<0.05). In conclusion our studies have shown that satellite cells proliferate in response to ischemia, produce paracrine factors that increase vascular cell migration in vitro, and lead to functional increases in perfusion in vivo. We believe these results demonstrate the critical role satellite cells play in collateral vessel formation and may be a potential new therapeutic approach for treating peripheral artery disease.Support or Funding InformationNIH F32HL124974 (LH)