Mechanistic models to guide redox investigations and interventions in musculoskeletal ageing.

Age is the greatest risk factor for the major chronic musculoskeletal disorders, osteoarthritis, osteoporosis and age-related loss of skeletal muscle mass and function (sarcopenia). Dramatic advances in understanding of the fundamental mechanisms underlying the ageing process are being exploited to understand the causes of these age-related disorders and identify approaches to prevent or treat these disorders. This review will focus on one of these fundamental mechanisms, redox regulation, and the role of redox changes in age-related loss of skeletal muscle mass and function (sarcopenia). Key to understanding the role of such pathways has been the development and study of experimental models of musculoskeletal ageing that are designed to examine the effect of modification of ROS regulatory enzymes. These have primarily involved genetic deletion of regulatory enzymes for ROS in mice. Many of the models studied show increased oxidative damage in tissues, but no clear relationship with skeletal muscle aging has been seen The exception to this has been mice with disruption of the superoxide dismutases and, in particular, deletion of Cu,ZnSOD (SOD1) localised in the cytosol and mitochondrial intermembrane space. Studies of tissue specific models lacking SOD1 have highlighted the potential role that disrupted redox pathways can play in muscle loss and weakness and have demonstrated the need to study both motor neurons and muscle to understand age-related loss of skeletal muscle. The complex interplay that has been identified between changes in redox homeostasis in the motor neuron and skeletal muscle and their role in premature loss of muscle mass and function illustrates the utility of modifiable models to establish key pathways that may contribute to age-related changes and identify potential logical approaches to intervention. Image 1 • Deletion of many regulatory enzymes for ROS in mice leads of increased oxidative damage in musculoskeletal tissues. • Only whole body deletion of Cu, Zn superoxide dismutase (SOD1) leads to an accelerated skeletal muscle ageing phenotype. • Tissue specific deletion of SOD1 in muscle or nerve of mice does not recapitulate the accelerated skeletal muscle ageing phenotype. • Expression of SOD1 in motor neurons of mice with whole body deletion of SOD1 rescues the accelerated skeletal muscle ageing phenotype. • Deletion of SOD1 in both motor neurons and skeletal muscle appears required to recapitulate the accelerated skeletal muscle ageing phenotype. [ABSTRACT FROM AUTHOR]