The goal of this project is to test the hypotheses that: 1) the degree of thermal impairment, and associated mechanisms of thermoregulatory control, in individuals with SCI will be related to the level of the injury and 2) individuals with SCI can counteract impaired thermoregulation by acclimating to a hot environment, perhaps via differing mechanisms depending on the level of the injury.  This goal will be accomplished by conducting a cross-sectional study to determine differences in the avenues of heat exchange among individuals with SCI with different lesion levels and a longitudinal study to determine the effects and mechanisms of heat acclimation in individuals with SCI. 

The goal of this project is to test a novel intervention designed to prevent cognitive decline in patients with Alzheimer’s disease.  This strategy involves two central tenets, each of which has a robust basic and clinical science background, but which have never been combined together in patients with Alzheimer’s Disease (AD): 1) the neuroprotective effect of erythropoietin (EPO); and 2) the salutary clinical effects of exercise training on AD mediated through brain-derived neurotrophic factor (BDNF) and insulin-like growth factor I (IGF-I). In this study, endogenous EPO production will be increased in the brain as well as in the plasma by mild intermittent hypoxic exposure (sleeping in a simulated high altitude environment about 8,000 ft., or the altitude of Vail, Colorado).  Exercise training will occur at sea level (normoxic environment) to increase BDNF and brain IGF-1 and to improve cardiovascular fitness and brain perfusion. We believe that this award winning (Peter van Handel award from the US Olympic Committee, and Research Award from the Wilderness Medicine Society) “Living High-Training Low” strategy developed in our lab for training athletes and proposed in this project has a great potential to bridge the findings from basic science to clinical research and lead to promising new therapeutic approaches to prevent, slow or even halt the progression of AD.

Chronic physical inactivity carries with it substantial mobidity, mortality and cost for our aging population. The key finding of the previous funding period for this competitive renewal was that sedentary aging leads to marked atrophy and stiffening of the heart. In contrast, Masters athletes had cardiac compliance that was indistinguishable from young controls. Thus life long exercise training prevented the stiffening of the heart that previously had been considered to be an inevitable consequence of aging.  Yet even prolonged and intense exercise training (up to 4-6 hours/week at the end of a year) failed to restore cardiac compliance in these healthy seniors. The global objective of this program is to determine the mechanism(s) of cardiac stiffening with sedentary aging, ascertain when in the aging process it occurs, and identify the minimal dose of sustained exercise training that preserves cardiac compliance over time. Our hypotheses are: Hypothesis 1a: A sedentary lifestyle leads to progressive atrophy and stiffening of the heart over a lifetime. Specific Aim 1a: To examine a cross-section of sedentary individuals over 5 decades from age 25 to 75 with comprehensive invasive and non-invasive measures of cardiac mechanics, relaxation, morphology and structural composition (lipid content and fibrosis). Hypothesis 1b:  A sufficient amount of exercise exists that will prevent this stiffening process, if started early enough, and sustained over time; this amount is below that required to be a competitive Masters athlete. Specific Aim 1b:  To identify healthy individuals who have consistently trained at 2 different doses: 30 min, 5 or more x/wk; or 30 min, 2-3 x/wk for at least 25 yrs.  The same structural and functional assessment will be performed as in aim 1.  Hypothesis 2:  Chronic plasticity of myocardial compliance in response to aging is dependent on long term changes in metabolism, leading to accumulation of myocardial triglyceride and/or advanced glycation end products (AGEs).  Specific Aim 2:  to:  a) measure myocardial triglyceride deposition using MRS in all the subjects from aim #1a and 1b encompassing a broad range of sedentary aging, and lifelong fitness levels; b) measure hemoglobin A1C as an index of protein glycation; c) perform delayed enhancement contrast MRI, and measure plasma markers of fibrosis. Hypothesis 3:  AGE crosslinks must be broken before an improvement in cardiac compliance can occur with exercise training in previously sedentary seniors.  The combination of an AGE crosslink breaker with exercise training will be superior to either intervention alone in reducing the cardiac stiffness associated with sedentary aging when initiated later in life. Specific Aim 3:  To examine a novel intervention using ALT-711 a specific breaker of the crosslinks of AGEs in parallel animal and human studies both alone and in combination with exercise training.

Lay summary – these experiments will provide new and important information regarding how the heart stiffens with age, and whether regular physical activity can prevent it.

After completion of these experiments, we will have obtained novel and clinically important information regarding the nature of the cardiac atrophy and stiffening associated with sedentary aging, including its age at onset and rate of change over the life span, as well as how much exercise is needed to prevent this process from occurring.  Mechanistic studies in both animals and humans will identify the unique mechanisms responsible for this process, focusing on the long term metabolic consequences of a sedentary lifestyle.  Finally, a novel intervention combining moderate (and sustainable) exercise training with a drug to break AGE crosslinks will be tested that may offer new hope for elderly patients who are suffering the clinical consequences of diastolic dysfunction.

A large fraction of cardiac output (i.e. greater than 50%) can be distributed to skin during heat stress, thus control of skin blood flow is vital for blood pressure regulation during a hypotensive challenge. Neural control of the cutaneous vasculature is unique relative to many vascular beds in that it is governed by both a sympathetic vasoconstrictor system and a separate sympathetic cholinergic active vasodilator system.  Adding to this complexity, direct local heating of the skin induces cutaneous vasodilation via an entirely different mechanism (i.e. non-neural and primarily nitric oxide dependent). Moreover, profuse sweating that occurs during heat stress contributes to impaired blood pressure control if plasma volume is sufficiently reduced. Sweating occurs through the engagement of a sympathetic cholinergic system that may or may not be related to the cutaneous active vasodilator system. Classically, these systems (i.e. vasoconstrictor, vasodilator, and sweating systems) have been viewed as being independent, without one system affecting the other.  However, preliminary data suggest significant interaction between these systems.  In heat stressed individuals the degree of interaction and the importance of this interaction with respect to blood pressure and temperature regulation remain unclear.  To this end, the projects outlined in this application will address the following three specific aims: 1) Test the hypothesis that substances released from the cutaneous active vasodilator nerve attenuate cutaneous vasoconstrictor responses through pre- and post-synaptic mechanisms; 2) Test the hypothesis that local heating attenuates cutaneous vasoconstrictor responsiveness through nitric oxide dependent and independent mechanisms; 3) Test the hypothesis that sweat glands are sensitized by mechanisms associated with local heating and through engagement of the cutaneous active vasodilator system.  These objectives will be accomplished by combining the innovative technique of intradermal microdialysis to locally deliver pharmacological agents and regionally sample interstitial fluid, with the simultaneous assessment of skin blood flow and sweat rate.  

Mitochondrial electron transport chain defects due to mitochondrial DNA (mtDNA) mutations are common and almost invariably affect skeletal muscle, resulting in a variety of symptoms including fatigability, weakness and rhabdomyolysis. While other organ systems may be involved, skeletal muscle symptoms often predominate and may cause severe disability or death. There is to date no accepted, effective therapy. Long term objective: To determine the safety and efficacy of two different modes of exercise training (endurance and resistance) as therapy for patients with mtDNA mutations. Preliminary studies from our laboratories provide strong support for both approaches but have also raised important concerns. Specific Aims: To investigate whether: 1) endurance training, by promoting mitochondrial proliferation, will increase wild type (normal) mtDNA copy number and whether this increase is responsible for improved mitochondrial oxidative capacity, exercise performance and quality of life; 2) a period of physical inactivity following prolonged activity (normally associated with a down-regulation of mtDNA copy number) will result in a disproportionate loss of wild type relative to mutant mtDNA copy numbers and correlate with decreased oxidative capacity and quality of life; 3) effects of exercise training influence oxidative stress and levels of detoxifying enzymes; 4) resistive training will induce activation of skeletal muscle satellite cells devoid of the mtDNA mutation through the process of hypertrophy or regeneration and improve mitochondrial oxidative capacity through incorporation of satellite cell-derived mitochondrial genes in patients with sporadic mtDNA.mutations. Research Design: All patients will undergo physiological exercise testing and muscle needle biopsy before and after 14 weeks of endurance or resistance training. Endurance training requires a third evaluation after 10 weeks of either continued training or physical inactivity. Training effects on mitochondrial genotype and function will be determined by changes in copy number of mutant and wild-type mtDNA and respiratory chain enzyme complex activity and assembly in individual muscle cells. Effects on exercise capacity will be determined by changes in peak capacity for exercise, oxygen utilization, muscle strength and quality of life. Given the management crisis for patients with mitochondrial myopathies, there is an immediate urgency to define appropriate recommendations for exercise training