Mechanisms Underlying Anabolic Effects of Cyclic Compressive Loading in Muscle

The loss of skeletal muscle mass is a main contributor to disability in numerous disease states and is also a predictor of mortality and a major factor in the loss of independence in the elderly. We propose that massage is a novel intervention to attenuate acute muscle atrophy or aid with regrowth after muscle loss in patients who are unable to perform exercise. Massage is a manual therapy modality extensively used clinically for pain relief and as a modulator of immune responses; however, very few investigations have addressed the actual underlying mechanisms of the beneficial effects of massage, mainly because of the lack of consistency in the applied load. Using an innovative cyclic compressive loading (CCL) device for small rodents, mimicking massage with a well-defined load, we showed that CCL elevated protein synthesis when administered during disuse or recovery after atrophy, and enhanced the regrowth response in the massaged limb, while no effect was seen in unperturbed rats. Surprisingly, we also found a positive regrowth response in the contralateral, non-massaged limb. We suggest that protein synthesis is elevated through mechanosensitive anabolic pathways, such as the focal adhesion complexes including focal adhesion kinase (FAK) and integrin-linked kinase (ILK), as well as stretch activated channels (SAC) in the massaged limb and that the growth effect in the non-massaged limb is mediated by a neuronal cross-over effect. Preliminary data also showed that the muscle regrowth response to massage was absent in aged animals and that the extracelluar matrix content was decreased with CCL. These preliminary data led to following hypothesis: Massage, in the form of CCL, exerts an anabolic effect on muscle directly through mechanosensitive pathways, as well as indirectly by neurally mediated mechanisms, to enhance muscle size in perturbed growth states. We will use CCL in rats and mice to study the muscle growth response using growth perturbations, i.e. disuse atrophy and regrowth after atrophy. Using genetic and pharmacological interventions three specific aims will address the hypothesis. In Aim 1 we will establish mechanisms for the attenuated growth response to CCL in muscles from aged compared to adult rats and test the hypothesis that muscles from aged rats show an attenuated response to CCL because of a stiffer extracellular matrix and a change in the pool of proteins synthesized. In Aim 2 the mechanosensitive pathways responsible for the growth response in skeletal muscle from adult rats after CCL will be investigated with particular attention to FAK and SAC. In Aim 3 we will test the hypothesis that the increase in protein synthesis and muscle size in the contralateral non-massaged limb after CCL is due to a sensory feedback-regulated cross-over effect, but will also investigate systemic-mediated actions. Results from these studies will indicate whether massage is a viable intervention for preventing the loss of muscle mass during disuse or promoting regrowth of muscle after atrophy while determining the underlying mechanisms for beneficial anabolic effects.