AS662 - MASS: Muscle and disease in postmenopausal women

Investigator Names and Contact Information

Hailey Banack (hrbanack@buffalo.edu)

Introduction/Intent

There is strong evidence linking sarcopenia with a myriad of poor health outcomes in postmenopausal women. Sarcopenia was previously defined simply as age-related loss of muscle mass, but newer definitions of sarcopenia include an assessment of muscle strength and/or performance. One of the greatest challenges in studying and understanding the relationship between sarcopenia and health outcomes is the difficulty in obtaining valid and accurate measurements of skeletal muscle mass. In clinical settings or research studies, muscle mass is typically measured by CT, MRI or DXA scan, but each of these methods require access to expensive specialized equipment and trained personnel. In this study we propose to use a novel method to measure muscle mass known as the creatine dilution method (D3-method). Research is needed to understand factors that cause and impact the progression of sarcopenia, and, in particular, low muscle mass, in postmenopausal women. Dysglycemia and insulin resistance have been identified as two factors that may affect muscle mass, strength, and function. Our central hypothesis is that long-term dysglycemia will result in sarcopenia, and sarcopenia will result in further declines in glycemic control as well as poor clinical and functional outcomes and mortality. Low muscle mass, in and of itself, will result in an increased risk of adverse outcomes, particularly among women with dysglycemia. This study will leverage currently available WHI resources and build on the second Long Life Study (LLS2) home visit. We propose to add the D3-method to the LLS2 protocol, and, in the years following the LLS2 visit, obtain repeat measures of muscle mass and dysglycemia remotely to study the dynamic, and time-varying relationship between these two factors. Our aims are to: 1) evaluate the extent of sarcopenia and understand its relation to dysglycemia and insulin resistance cross-sectionally in postmenopausal women in LLS2; 2) use stored blood samples from the WHI and LLS1 to examine the effect of long-term (25+ year) trajectories of dysglycemia and insulin resistance on sarcopenia at LLS2, and (3) examine the prospective effects of sarcopenia and dysglycemia on CVD, functional outcomes (falls, fractures, activities of daily living, and mortality. The proposed study fills a critical gap in our knowledge about sarcopenia and dysglycemia, two highly prevalent, and modifiable, risk factors for adverse outcomes in older women. The findings of the proposed study will lay the foundation for future intervention studies to further the NIA strategic goal of improving the health, well-being and independence of adults as they age.

SPECIFIC AIMS

The creatine dilution method is a direct measure of skeletal muscle mass that has the potential to transform our understanding of sarcopenia in older women. Sarcopenia is an age-related progressive muscle disease characterized by: 1) low muscle mass, 2) low muscle strength, and 3) impaired physical performance. One of the greatest barriers to understanding the clinical relevance of sarcopenia in older adults is the challenge of obtaining valid measures of skeletal muscle mass. Until recently, measuring muscle mass required expensive, specialized equipment, and highly trained technicians. This limited our ability to obtain longitudinal data and repeat measurements of muscle mass in large research studies of older adults. Muscle mass is also largely ignored in clinical settings, owing to measurement challenges. Dual energy x-ray absorptiometry (DXA) is frequently used to measure muscle mass, but studies relating muscle mass from DXA to outcomes are equivocal. This has led many to question whether muscle mass is a key predictor of clinical and functional outcomes in older adults, or whether muscle strength and quality are more relevant. Recently, a novel hypothesis has been proposed1: DXA derived muscle mass is a poor approximation of true skeletal muscle mass; a direct measure of muscle mass (e.g., the creatine dilution method) is required to truly understand the potential negative impact of low muscle mass in older adults. The creatine dilution method has been used to measure muscle mass in older men and demonstrated strong associations with physical function, incident falls, and mobility limitations, whereas DXA derived muscle mass demonstrated no association. No study to date has used the creatine dilution method to examine the relation between muscle mass and clinical outcomes, such as CVD or mortality, nor has work been done in postmenopausal women, a uniquely high risk group. As well, in older women, sarcopenia may compound the increased risk of functional impairment and mortality associated with diabetes, dysglycemia, and insulin resistance. This project will leverage 25 years of data from the Women’s Health Initiative (WHI), and include the collection of new measures of muscle mass, strength, and physical function to address a critical gap in our understanding of the role of sarcopenia in aging women’s health.

Our long-term goals are to improve the characterization of the components of sarcopenia, identify population sub-groups (e.g., certain racial/ethnic groups) at highest risk for adverse outcomes related to sarcopenia, and ultimately develop effective interventions for the prevention and treatment of sarcopenia. Our overall objectives in this application are to: (i) compare the association of muscle mass and muscle quality with physical function and clinical outcomes in postmenopausal women, and (ii) examine the dynamic relationship between sarcopenia, dysglycemia, and mortality. Our central hypothesis is that long-term dysglycemia will result in sarcopenia, and sarcopenia will result in further declines in glycemic control as well as poor clinical and functional outcomes and mortality. Low muscle mass, in and of itself, will result in an increased risk of adverse outcomes, particularly among women with dysglycemia. The rationale for this project is that a determination of the role of muscle mass, measured by the creatine dilution method, and sarcopenia, as a mediator of the relationship between dysglycemia, and clinical outcomes is likely to offer a strong scientific framework for the development of screening and intervention programs. To attain the overall objectives, the following specific aims are proposed:

Specific aim 1: Evaluate the extent of sarcopenia and its specific components (muscle mass, strength, and physical function) in postmenopausal women in the Women’s Health Initiative

• Aim 1a: Examine the cross-sectional association of sarcopenia (muscle mass, strength, and physical function) with dysglycemia and insulin resistance

Specific aim 2: Use longitudinally available blood samples to determine the impact of dysglycemia and insulin resistance on sarcopenia and its specific components (muscle mass, strength and physical function) in postmenopausal women

Specific aim 3: Determine the relationship between sarcopenia and its specific components (muscle mass, strength, and physical function) on all-cause, and cause-specific mortality

• Aim 3a: Evaluate the effect of sarcopenia on dysglycemia and incident diabetes
• Aim 3b: Examine the extent to which sarcopenia mediates the relationship between dysglycemia and falls, fractures, activities of daily living, incident cardiovascular events, and mortality