Kevin K. McCully, Ph.D - US grants

DESCRIPTION: (provided by applicant) Physical inactivity after spinal cord injury (SCI) leads to low exercise capacity and increased risk of cardio vascular disease mortality. Exercise conditioning, which moves an individual from the lowest to the next quintile for aerobic fitness, reduces mortality. Our long-term goal is to develop therapies that maintain cardiovascular health after SCI. We have shown that the major adaptation of skeletal muscle within 6 months of SCI is atrophy. We reversed this sarcopenia using our simplistic electromyostimulation (EMS) conditioning protocol. In contrast, it has been difficult to evoke hypertrophy in chronic patients. We hypothesize, therefore, that a meaningful increase in aerobic exercise capacity during functional electrical stimulation (FES) exercise will occur in short term but not chronic patients after EMS conditioning because the limitation in peak VO2 after SCI is a small active muscle mass. Metabolism/perfusion mismatch that results in fatigue and low force during EMS may explain the limited hypertrophy in chronic SCI. Lack of up regulation of endogenous growth factors, i.e., IGF1, which we have shown to occur in able-bodied individuals after EMS, may also limit muscle growth. We will also test these hypotheses. Patients within 4 to 8 months of or at least 3 years after complete SCI will be examined in studies with the following specific aims: 1) FES, which evokes dynamic knee extension exercise of m. quadriceps femoris, will be done to measure peak VO2 before and after EMS conditioning designed to evoke hypertrophy; 2) 12 weeks of EMS conditioning will be used to assess the hypertrophic capacity of m. quadriceps femoris. Coupled lengthening and shortening actions will be evoked. Fiber and whole muscle size will be assessed in biopsies of m. vastus lateralis and magnetic resonance images of m. quadriceps femoris; 3) Fatigue, blood flow and metabolism to perfusion matching of m. quadriceps femoris will be assessed. Force will be measured during EMS. Limb blood flow will be measured after cuff ischemia using duplex Doppler. Muscle oxidative capacity will be assessed using biopsies (metabolic enzymes) and near infrared spectrophotometry (state of oxygenation); and 4) Up regulation of component(s) of the skeletal muscle IGF-1 autocrine/paracrine system and responsiveness of satellite cells to IGF- 1 signaling will be measured after EMS of m. quadriceps femoris. These studies are significant. They assess pathophysiology (perfusion /metabolism mismatch and/or lack of up regulation of muscle growth factors), impairment (inability to evoke hypertrophy) and functional limitation (low aerobic exercise capacity) which lead to increased risk of cardiorespiratory disease mortality

DESCRIPTION (provided by applicant): This proposed research is a revised competing continuation of a previous award. Our previous research showed that surface neuromuscular electrical stimulation (SNMES) can markedly increase muscle mass in individuals with complete spinal cord injury (SCI). We found pilot data that suggested that SNMES can also increase insulin action after complete SCI who are glucose tolerant. The general aim of this proposal is to extend our research to test whether exercise therapy can improve insulin action in complete SCI individuals who are either diabetic (DIA) or have impaired glucose tolerance (IGT). The specific aims are: 1) Can 3 months of resistance or endurance exercise therapy be affective at "treating" IGT or DIA in complete, SCI individuals;and 2) What are the physiological adaptations (increased muscle mass, decreased fat mass, increased muscle endurance) are responsible for the improved insulin action following SNMES-induced exercise therapy. 100 subjects (84 to start the program, 78 expected to finish) with complete SCI (either paraplegic or quadriplegic) who are either IGT or DIA, 18 to 55 yrs of age, will be studied over the next 5 yrs. The resistance training will consist of knee extensions with ankle weights, two sessions of 40 lifts per week for 3 months. The weight used will be increased as needed. Endurance exercise therapy will use twitch stimulations for 30 minutes three times per week. A control group (no exercise) will be used for comparison. The following techniques will be used to assess the efficacy of the therapies;an oral glucose tolerance test for insulin action, magnetic resonance imaging for muscle size and lipid deposits, and SNMES for the fatigue tests. Rejection of the null hypothesis will show that those with a complete SCI can use either residence-based, self-administered resistance or endurance exercise therapy to treat IGT/DIA and reduce the risk of cardiovascular disease. In addition, physiological adaptations that best predict changes in insulin action will be determined. A blocked design will be used to separately evaluate IGT and DIA. This research will address methods to prevent diabetes which is an important health problem in SCI. This study will also use practical self-administered exercise protocols, and will test links between insulin action and modifiable physiological functions. Thus, this research has the potential to significantly benefit people with spinal cord injuries.