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Muscle-bone interaction: bone response to physical exercise with or without impact load in mice with IGF-1 hyperexpression in type II skeletal muscle fibers

Abstract

It is known that the elastic deformation imposed on bones by muscle contraction stimulates bone formation, while inhibiting resorption, which favors the gain of bone mass. Considering that bone and skeletal muscle tissues secrete factors (osteokines and myokines, respectively) that act in other tissues or organs via paracrine and endocrine mechanisms, a new paradigm has been established that there are biochemical interactions between muscle and bone, besides the undeniable biomechanical interaction. Considering that insulin-like growth factor type 1 (IGF-1) has anabolic actions in both bone and muscle tissue, we investigated, in a previous study, the hypothesis that muscle-derived IGF-1 could act on bone through biochemical mechanisms. Thus, we studied transgenic mice that hyperexpress a muscle isoform of IGF-1 (mIgf-1) in type II skeletal muscle fibers (TgIGF1 mice), which results in hypertrophy of these fibers. We observed that TgIGF1 females showed improvements in the femoral bone microarchitecture, mainly at 3 and 5 months of age, versus wild-type (WT) mice, exactly when TgIGF1 animals presented skeletal muscle hypertrophy, suggesting mechanical muscle-bone interaction. To discriminate possible biochemical effects of mIgf-1 from the mechanical effects of hypertrophied skeletal muscles, we evaluated the impact of disuse on the musculoskeletal phenotype, using the tail suspension protocol, where the hind limbs remained without ground contact for 14 days. This condition resulted in similar muscle atrophy between the TgIGF1 and WT animals, showing that the hyperexpression of mIgf-1 does not prevent or minimize muscle atrophy. Unexpectedly, the tail suspension caused significant deterioration in the trabecular and cortical bone microarchitecture of TgIGF1 mice, while it did not affect the femoral bone of WT females. These findings suggest biochemical and negative actions of mIgf-1 in bone microarchitecture; while suggesting the hypotheses that the osteogenic effects of muscle IGF-1 depend on mechanical stress, and that the absence of mechanical load converts the anabolic effects of IGF-1 into catabolic. Given these hypotheses, it is important to question whether only the mechanical stress imposed on bones by muscle contraction is sufficient for the osteogenic effects of muscle IGF-1 to occur; or whether ground reaction forces (impact loads) are also required. The present study aims to investigate whether mechanical stress is necessary for muscle IGF-1 to promote anabolic actions in the bone tissue, in addition to investigating the type of mechanical stress (muscle contraction with or without impact load) necessary for the occurrence of these possible anabolic actions. Therefore, we will evaluate the structural and biochemical responses of bone and skeletal muscle to physical activity with and without impact load (running and swimming, respectively) in female TgIGF1 and Slv mice. The results of this study should bring important contribution to the understanding of the role of IGF-1 and physical activity in muscle-bone interaction, besides contributing to the understanding of the morphophysiology of bone and muscle tissues, acting as a functional unit. Such understandings will certainly open windows of therapeutic opportunities for the prevention and treatment of osteoporosis, sarcopenia and ostesarcopenia; in addition to contributing to rehabilitation therapies of the musculoskeletal system. (AU)

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