Theodore F. Towse, Ph.D. - US grants

DESCRIPTION (provided by applicant): Sporadic Amyotrophic lateral sclerosis (SALS) is a neurodegenerative disease that targets upper and lower motor neurons and causes motor unit loss;severe, progressive muscle atrophy;and almost inevitably, death. Multiple lines of evidence, derived primarily from animal models of ALS, suggest that reduced skeletal muscle oxidative ATP-synthesis ("mitochondrial dysfunction") manifests itself early in the disease process and may contribute to these neurodegenerative processes. However, whether or not skeletal muscle mitochondrial dysfunction is present in human ALS patients and what role it may play in neurodegeneration remains equivocal. A limitation to testing the hypothesis of skeletal muscle mitochondrial dysfunction in human SALS patients is the primary technique used to date is muscle biopsy followed by histochemical analysis. The biopsy technique is prone to false negatives, due to the small sampling volume, and the invasive nature of the technique makes it inappropriate for use in a disease marked by muscle wasting. However, phosphorus magnetic resonance spectroscopy (31P-MRS) provides a powerful alternative for assessing mitochondrial function in vivo, has been used successfully to study mitochondrial function in other pathological conditions involving muscle, can acquire data from localized anatomical regions, and is non- invasive and non-destructive. Therefore, the overall goal of this project is to use 31P-MRS to explore the presence and whole-body energetic consequences of skeletal muscle mitochondrial dysfunction in SALS patients and to relate these measures of mitochondrial function to clinical measures of disease state. In order to accomplish this objective, we have set the following specific aims: Specific Aim 1: To test the hypothesis that resting skeletal muscle ATP-synthesis rate will be similar in SALS patients and controls in spite of higher resting energy expenditure (REE) in SALS patients. To do so, we will measure resting skeletal muscle ATP- synthesis rate using saturation transfer 31P-MRS and REE using indirect calorimetry in SALS patients and age-, gender-, body mass index (BMI)-, and physical activity- matched controls. Specific Aim 2a: To test the hypothesis that maximum skeletal muscle aerobic ATP-synthesis rate will be lower in SALS patients than in matched controls. To do so, we will use 31P-MRS to measure maximum skeletal muscle aerobic ATP-synthesis rate following a series of maximal isometric contractions in SALS patients and matched controls. Specific Aim 2b: To test the hypothesis that the ATP cost of contraction is lower in SALS patients versus healthy controls. To do so, we will measure the ATP cost of skeletal muscle contractions in SALS patients and matched controls using 31P-MRS. By testing hypotheses concerning the uncoupling of skeletal muscle ATP-synthesis to total energy expenditure (Aim 1), impairments to the maximum rate of ATP-synthesis (Aim 2a), and the energetic cost of contraction (Aim 2b), the proposed studies will provide the first known systematic investigation of the presence and nature of skeletal muscle mitochondrial dysfunction in human SALS patients. PUBLIC HEALTH RELEVANCE: Sporadic Amyotrophic lateral sclerosis (SALS) results in break down of the nerves that control skeletal muscle, resulting in severe muscle wasting. How and why these nerves die remains unclear;however, it may be related to a defect in the skeletal muscles'ability to use oxygen. The aim of this study is to determine if the muscles of SALS patients have a diminished capacity to use oxygen and if this is related to nerve loss.

? DESCRIPTION (provided by applicant): Brown adipose tissue (BAT) has garnered widespread attention recently due to its potential involvement in weight maintenance, blood lipid metabolism and glucose homeostasis. Although research in animals (mainly mice and rats) supports an inverse relationship between BAT and the development of metabolic syndrome, very little is known about the function of BAT in humans (hBAT). The reason for our limited understanding may be due in part to the lack of appropriate techniques for studying hBAT. The technique most commonly used to study hBAT is 18F-FDG PET, which has come under scrutiny because it only detects BAT that takes up glucose (not the preferred energy substrate of BAT). Therefore, 18F-FDG PET likely underreports the prevalence of hBAT. Our group has recently developed robust MRI-based techniques to study hBAT non- invasively, and without the use of radioactively labeled tracers. We will use these techniques to provide an accurate assessment of the prevalence and thermogenic activity of hBAT as well as to investigate the influence of physical activity, sex, age, body composition and diabetes status on hBAT. We will study hBAT in adults using two magnetic resonance imaging (MRI) techniques available on a 3 Tesla human MRI scanner. First, fat signal fraction (FSF) maps obtained from fat-water separated MRI can localize hBAT and estimate BAT volume and mass. Maps of FSF can distinguish BAT because it contains a higher proportion of water compared to white adipose tissue (WAT), while also containing a higher lipid fraction than lean tissue. The second MRI technique is a recently developed advanced fat-water thermometry technique that measures the absolute shift in the water peak resulting from a change in temperature. Lipid signals, which are not affected by temperature, serve as a built-in reference allowing the measurement of absolute temperature in tissues containing both water and lipid signals - a hallmark of brown adipose tissue. Subjects will also undergo indirect calorimetry. Mass and the thermogenic activity of hBAT will be assessed in each subject using two distinct experimental protocols using either cold-stimulation or a meal-challenge. In this study, we will pursue the following three Specific Aims: [1] Investigate the impact of physical activity and sex on BAT mass and activity in adult humans. [2] Investigate the impact of age and body composition on BAT mass and activity in adult humans. [3] Investigate the impact of diabetes on BAT mass and activity in adult humans. Impact: Reliable characterization of hBAT mass and activity in healthy and clinically relevant subjects is critical for the pursuit of longitudinal interventional studies by clinical investigatos to therapeutically enhance hBAT to counteract metabolic diseases.