6. Project Summary Abstract Muscle wasting is common in patients with advanced chronic kidney disease (CKD) and adversely affects morbidity and mortality. Multiple factors cause the wasting including resistance to or deficiency of anabolic hormones such as growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Also, the usual sedentary life-style of advanced CKD patients predisposes them to muscle wasting and this is induced or worsened when these subjects are immobilized in bed because of illness. Preliminary data indicate that disuse atrophy may be exaggerated in CKD and that recovery may be impaired. The goal of the proposed study is to generate a more complete understanding of the mechanisms behind muscle wasting and the exaggerated atrophy that occurs during disuse in uremia. The study will be carried out with muscle biopsied from normal and end-stage CKD patients, CKD rats with muscle wasting, and CKD rats with disuse atrophy induced by immobilization. Specific Aim 1. To evaluate the effect of uremia on GH mediated signal transduction in human skeletal muscle. Animal studies indicate that muscle wasting may be due in part to impaired GH mediated signal transduction. The proposed study will determine whether this is also true for humans. This is an ongoing study. Specific Aim 2. To test the thesis in rats that chronic uremia worsens the skeletal muscle atrophy that occurs following disuse and attenuates recovery after the affected limb is mobilized. Another aim is to elucidate the mechanisms involved. It is postulated that the exaggerated atrophy and impaired recovery is mediated largely because of: (1.) depressed local IGF-1 production and increased myostatin production, (2.) impaired activation of PI3K/Akt/mTOR signaling, with attenuation of the downstream pathways that suppress degradation and activate protein synthesis, and (3.) depressed AMP-activated protein kinase (AMPK) activity. Specific Aim 3. To test in rats whether any of the following maneuvers will attenuate uremic muscle wasting, reduce disuse atrophy, and accelerate recovery. (1.) Treatment with recombinant GH to overcome resistance to the hormone and thereby stimulate IGF-1 production. (2.) Administration of recombinant IGF-1 to overcome IGF-1 deficiency and resistance to the hormone. (3.) Activation of AMPK with an AMPK agonist (AICAR) to mimic endurance exercise. These studies should provide new insight into the mechanism of muscle wasting in uremia and provide the basis for achieving the long-term goal of developing strategies for the more effective treatment of muscle wasting in uremia. Furthermore, since catabolic states with muscle wasting are common in other hospitalized VA patients, including those immobilized post-trauma and in the elderly, our approach holds the long-term potential of improving the management of veterans not only with advanced CKD, but with other illnesses. PUBLIC HEALTH RELEVANCE: 7. Project Narrative Catabolic states with muscle wasting are common not only in malnourished veterans with advanced renal failure, but also in other hospitalized VA patients, especially the elderly, in the young with post-traumatic injury, and in patients with heart failure or liver cirrhosis, and this has an adverse effect on morbidity and mortality. Since these illnesses often require bed-rest or limited mobilization, disuse atrophy of muscle sets in and worsens their condition and slows recovery. There is very little information on the impact of disuse on the muscle wasting in the patient with advanced kidney failure, even though hospitalization is frequent. The studies we have proposed in kidney failure patients and with an animal model of kidney failure and disuse atrophy should provide new insight into the mechanism of muscle wasting and recovery from disuse atrophy in kidney failure. Included in the animal studies is an evaluation of different treatment regimens to prevent muscle wasting and accelerate recovery from disuse. Overall the knowledge generated should provide the basis for achieving our long-term goal of developing strategies for the more effective treatment of muscle wasting in kidney failure patients and thereby improving the health and outcome of these patients. Furthermore since catabolic states are common in other hospitalized veterans, especially those immobilized post-trauma and the elderly, our approach holds the long- term potential of improving the management of patients, veterans and non-veterans, not only with advanced kidney failure, but also with other illnesses.