The effects of dihydrotestosterone on amino acid transport in ageing mammalian skeletal muscle fibres

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Ageing leads to a gradual decline in skeletal muscle mass and strength, commonly referred to as sarcopenia. Sarcopenia occurs mostly in people >80yrs (and rodents >2 years old) and its consequences include inactivity, increased susceptibility to falls and eventually to loss of independence. As the number of people over 80yrs in the United Kingdom is expected to double in the next 20 years, from 2.7 million in 2006 to 5.4 million by 2031, the percentage of the population suffering from sarcopenia and the demands this imposes on the NHS and society in general is expected to rise accordingly. Despite its physical and socioeconomic importance, little is known about the causes of sarcopenia. In this study we propose that it occurs because of a decrease in the ability of skeletal muscle cells to transport amino acids (the building blocks of proteins ) into and out of the cells. We also suggest that this decline is due to a reduction in the number of the transporters/pumps that move amino acids into and out of the cells or is due to a decrease in the concentration of hormones such as the male sex hormones that normally stimulate these pumps.To test these suggestions we plan to investigate; (1) the effects of age on the number of amino acid transporters and their ability to move amino acids into and out of mouse skeletal muscle cells. (2) Whether treating muscle cells with dihydrotestosterone (DHT), the active metabolite of testosterone, can reverse these age-dependent changes. (3) Finally we will test whether treating mice >560 days old with DHT for 4 weeks reverses/slows down sarcopenia. We will also investigate whether DHT treatment increases the transport amino acids and the synthesis of new proteins.Three types of experiments will be used in the study. The first type will use mice of different ages (range 60-730 days) kept under normal laboratory conditions. Small muscle fibre bundles isolated from the edl and soleus muscles of each age group will then be used to investigate the effects of age on the expression and physiological function of various amino acid transporters and the cellular and molecular mechanisms underlying these changes.Most previous studies have investigated the effects of testosterone treatment on skeletal muscle mass and strength and no studies have investigated those of DHT treatment. Therefore, the second experiment will investigate the effects of treating young, old and senescent mice with DHT for at least 4 weeks. Small muscle fibre bundles isolated from the edl and soleus of treated and untreated mice will then be used to investigate the effects of DHT treatment on skeletal muscle mass, strength, the expression and function of various amino acid transporters, the uptake of isoleucine (Ile) and MeAIB and the incorporation of Ile into proteins.In the third experiment, the acute effects of DHT treatment on force production, amino acid transport and incorporation into proteins in muscle fibre bundles isolated from the edl and soleus of senescent mice will be investigated. The cellular and molecular mechanisms underlying these effects will also be investigated.Most of these experiments will be performed using CD1 mice because they are inexpensive, have similar genetic variations as normal mouse and human populations and suffer from severe sarcopenia from 24 months onwards.The results from these experiments will provide important information on the role a decline in amino acid transport and reduced bioavailability of anabolic steroids, play in sarcopenia. They will also increase our understanding of the changes that occur in skeletal muscle with ageing and the mechanisms underlying these changes. They will also provide information on whether DHT treatment can delay/slow the development of sarcopenia as well as the mechanisms underlying its effects. These findings will be important in the development of new ways of managing sarcopenia in the future.