Integrative and adaptive responses.

Darwin is considered the father of modern evolutionary biology by recognizing the importance of integrative and adaptive structural and physiological responses in living organisms. In his textbook Principles of Biology (1864), Herbert Spencer succinctly stated the essence of Darwin’s theory of natural selection as “survival of the fittest”–terminology later adopted by Darwin. Two additional quotes frequently but incorrectly attributed to Darwin also succinctly emphasize the main premise of natural selection: “In the struggle for survival, the fittest win out at the expense of their rivals because they succeed in adapting themselves best to their environment,” and, “It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change” (see Darwin Project at University of Cambridge). Although the theory of natural selection (evolution) has undergone revision by modern biologists, it is widely recognized that adaptations occur across organ systems in an integrated response. Such integrated adaptive responses are clearly evidenced in the interactions between muscles and bone–a topic covered by three invited reviews in this issue of Physiology. We also now recognize that adaptive responses are highly complex, sometimes involving epigenetic modifications in DNA that are heritable, and are thereby preserved in future generations. Comparative, evolutionary, and integrative physiologists are at the forefront of new discoveries in this important area, and such discoveries will have profound impact on our general understanding of biology and physiology. Indeed, great strides have already been made and have led to the development of novel therapeutic strategies that advance medical practice. Aging is associated with the development of sarcopenia in skeletal muscle and osteoporosis in bone; however, the extent of the physiological relationship between them as we age is not fully understood. Aging-induced decline in muscle size and contractility are thought to contribute to catabolic alterations in bone, but the changes in bone due to aging also profoundly alter its response to musclederived stimuli. In their review (6), Novotny and associates provide an overview of the alterations in muscle and bone that occur with aging. Furthermore, they discuss the mechanical, cellular, and molecular mechanisms that may impact the muscle-bone relationship. Such changes include reduced osteocyte viability and reduced proliferative capacity of osteoprogenitors in the periosteum, which attenuate the response of bone to muscle contraction either through mechanical or nonmechanical stimuli. Loss of motoneurons, decreased muscle fiber size, and decreased muscle protein synthesis in muscle with age all negatively impact the contractile machinery, force-generating capacity, and secretome of aged muscle. In addition, they highlight therapeutic strategies aimed to enhance the anabolic capacity of the periosteum in conjunction with therapeutics to increase the forceand power-generating capacity of aged muscle, pointing out that these strategies could significantly improve musculoskeletal health and function in the elderly. Such approaches may potentially reduce the risk for falls and therefore decrease the incidence of bone fracture, disability, and death in aging adults. Bone is a very dynamic and metabolically active organ that is composed primarily of calcium-phosphate mineral and type I collagen. Calcium has helped provide the means for exploitation of new habitats by contributing to diverse skeletal structural adaptations, which promote calcium and mechanical homeostases in extant vertebrates. Osteocytes and bone remodeling first appeared in the dermal skeleton of fish, and subsequently adapted to various challenges in terrestrial animals occupying diverse environments. In their review (3), Doherty and Donahue discuss the physiology of bone and its role in mechanical and calcium homeostases from an evolutionary perspective, focusing on adaptations to unique and extreme physiological conditions. The evolutionary physiology of bone informs our understanding of the skeletal diversity in extant vertebrates and may provide clues for possible treatments for skeletal diseases, including osteoporosis. Sex differences in skeletal muscle structure and function are poorly understood. Historically, most scientific studies have focused on male animals and men; thus many diagnostic techniques and treatment standards are based on a characterization in males, whereas major differences in females are largely ignored. For example, women typically display greater resistance to fatigue compared with males. In their review (4), Haizlip et al. discuss differences in skeletal muscle fiber-type composition and contractility between sexes and how these differences may be hormonally regulated. Understanding and acknowledging sex differences in skeletal muscle structure and function is relevant to the development of diagnostic techniques, treatment, and identification of disease susceptibility. Microscopy is clearly a powerful tool in physiological investigations. Indeed, nearly every organ system has now been studied microscopically, thereby tying function to structure. Recently, the development of intravital imaging has enabled the continuous study of live cellular events in their natural environment, providing dynamic information that cannot be accurately obtained with traditional histological assays. In their review (1), Choi et al. discuss how intravital microscopy has provided optical access to various organs in the mouse and how this has been facilitated by the implantation of transparent windows and the use of miniature endoscopic probes. The lessons learned from intravital imaging have greatly enriched our understanding of human physiology in normal and diseased states. For example, recent studies have elucidated mechanisms of cancer cell metastasis in the liver, stem cell regeneration in the small intestine, and reperfusion injury in the heart and lungs. Intravital imaging techniques have also been applied directly to the clinic, such as endomicroscopy to diagnose gastrointestinal abnormalities. With continued collaboration between biologists, engineers, and physicians, intravital microscopy is PHYSIOLOGY IN PERSPECTIVE Gary Sieck, Editor-in-Chief Mayo Clinic, Rochester, Minnesota PHYSIOLOGY 30: 6–7, 2015; doi:10.1152/physiol.00053.2014