Aquaporins: A hole in our understanding of hydrogen peroxide regulation

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Lay Summary:There has been great interest in the idea that free radicals (and other chemicals that are collectively called reactive oxygen species "ROS") contribute to loss of muscle performance and indeed a whole range of age-related disorders. We have lots of evidence that excessive production of one of these reactive species, hydrogen peroxide, can be damaging to muscle structure and function. Since loss of muscle mass and strength is a leading cause of immobility in older people in the developed world it is surprising that there are no published studies of how hydrogen peroxide passes through skeletal muscle cell membranes (sarcolemma) and no previous attempts to see if blocking such transport can preserve muscle function. In this project, we will close this fundamental knowledge gap.In the past few years, it has become clear that the major route of transport of hydrogen peroxide through membranes in various non-muscle cells is the family of membrane protein channels called "aquaporins". Our pilot data confirm that aquaporins facilitate hydrogen peroxide membrane transport in skeletal muscle too.The existence of aquaporin proteins has been known for about 25 years now, but they were first thought of simply as the route of passage of water through membranes. In fact, the characterisation of these so-called "water channels" gained Prof Agre a Nobel Prize in 2003. Surprisingly, therefore, there have been only a few studies of muscle aquaporins and no studies of their role in the regulation of muscle hydrogen peroxide at all. This is perhaps because previously there had been a lack of appropriate research tools to study hydrogen peroxide in fine detail.Our group's unique combination of novel molecular tools and muscle degeneration models now allow us to answer a number of fundamental and important biological questions about hydrogen peroxide transport in skeletal muscle.(a) Which of the aquaporins are most important for hydrogen peroxide spread in muscles?(b) Does aquaporin regulation of hydrogen peroxide change with age or muscle injury?(c) Does block of muscle aquaporins promote maintenance of muscle function after neuromuscular injury? It is often assumed that free radicals are "bad" and "antioxidants" are good and that therefore block of aquaporins or elimination of peroxide would be beneficial to muscle function, however, this is a very simplistic view and needs validating. For example, some recent data support the possibility that hydrogen peroxide transport is critical to high-performance muscle function. Furthermore, there are dozens of common dietary substances that can block some of the aquaporin channels, many of these are so-called plant "polyphenols" and, coincidentally, better known for their antioxidant properties. So we need to answer these widely important biological questions urgently so that dieticians and those in medical research can start to develop more informed treatment strategies for age and injury-related muscle loss.