Targeted therapies for aging-related mobility disability are urgently needed to preserve quality of life and pre- vent morbidity/mortality in the rapidly expanding aging population. Progressive decline in mobility with aging has been partially attributed to loss of skeletal muscle (SM) mass and function, as well as an increase in the quantity of adipose tissue (AT). The quality of AT and AT-secreted factors are also likely to influence this pro- cess, yet meager evidence exists for this notion. Cellular senescence, a phenomenon by which normal healthy cells cease to divide and therefore become programmed for cellular death, occurs in adipose tissue and is as- sociated with poorer mobility. Furthermore, secreted factors from AT, potentially from senescent or dying cells, induces insulin resistance and atrophy in human skeletal muscle cells. Collectively, these data demonstrate that AT quality (i.e., structure and function) can directly impact skeletal muscle function. This adipose-skeletal muscle crosstalk has been increasingly implicated in poor functional and metabolic outcomes in younger hu- man populations. The unique contributions of AT structure and function and AT-secreted factors to mobility de- cline and skeletal muscle function in the context of human aging have not been addressed. The proposed stud- ies will fill a critical knowledge gap by directly assessing structural and functional components of AT in aging and using their associations with mobility to identify AT-secreted proteins that negatively impact skeletal mus- cle function. The long-term goal of this ancillary study is to leverage and add to the outstanding resources of the parent SOMMA project to understand the contribution of AT quality, AT-secreted factors and AT-skeletal muscle crosstalk to mobility disability and other complications of aging in humans. Our overall objective is to identify key structural and functional components of AT quality - including necrosis, senescence, inflammation, self-renewal and metabolic flexibility - and AT-secreted proteins that influence mobility via direct effects on skeletal muscle. We hypothesize that AT structure and function influences AT-secreted proteins that contribute to aging-related mobility outcomes by directly impacting skeletal muscle function. The stated purpose of Aim 1 is to determine which structural and functional components of AT are associated with slower walking speed. We posit that increased cellular senescence, increased necrosis, increased inflammation, decreased capacity for self-renewal and metabolic inflexibility will be associated with slower walking speed.
For Aim 2, we antici- pate that incubation of human muscle cells with known and novel secreted proteins - identified through stand- ard immunoassay panels and unbiased proteomics and shown to be associated with aberrations in AT struc- ture and/or function - will worsen mitochondrial respiration, increase oxidative stress, decrease contractility and muscle cell diameter. This work will have a positive translational impact by improving strategies for prevention and/or treatment of aging-related mobility disability and by promoting knowledge and facilitating future studies to understanding AT-skeletal muscle crosstalk across the lifespan.
The SOMMA project is a large-scale trial designed to determine key biological properties of skeletal muscle that are related to incident major mobility disability, declines in mobility and declines in fitness in older adults (> 70yr) over the course of three years, while also collecting adipose tissue and blood. The experiments proposed herein will examine the influence of adipose tissue (AT) structure and function on AT-secreted proteins that are related with mobility disability and can directly impact skeletal muscle function. The proposed work will also quantify the AT-secreted proteins in circulation that are found to directly affect skeletal muscle function, as well as contribute all excess biospecimens to the parent SOMMA project biorepository for future use.
