Effects of aging and exercise training on intermuscular adipose tissue (IMAT) in MoTrPAC

Intermuscular adipose tissue (IMAT) is marbled within skeletal muscle and appears to play a key role in the
age-induced risk of type 2 diabetes and sarcopenia. What is not known is how IMAT promotes decreased
muscle insulin sensitivity and sarcopenia. There is a critical need to address this gap in knowledge to
understand how IMAT contributes to the risk of aging-induced sarcopenia and diabetes to inform
intervention strategies. The overall objective for this project is to determine the impact of aging and
exercise training on IMAT secretion of fibronectin and myostatin and the cellular composition of IMAT. Our
central hypothesis is that IMAT secretion of fibronectin promotes muscle insulin resistance, and IMAT
secretion of myostatin promotes sarcopenia, both of which are intensified by aging and diminished by
exercise. The rationale that underlies the proposed research is that clarifying the extent to which aging and
exercise training alter the IMAT secretome and cell composition will inform development of interventions to
modify IMAT and improve muscle mass, strength, and insulin sensitivity in older individuals. We propose
two specific aims: Specific Aim 1. Determine the impact of age and exercise training on IMAT secretion of
fibronectin, IMAT fibroblast composition, and the importance of fibronectin in the IMAT secretome to
decrease insulin sensitivity in vitro. Preliminary data inform our working hypothesis that IMAT secretion of
fibronectin increases with age due to greater fibroblast content, decreases muscle insulin sensitivity, and is
attenuated after exercise training. In vitro experiments will measure the extent to which IMAT fibronectin
secretion explains IMAT-induced muscle insulin resistance. We propose a coordinated effort between
Colorado and Florida MoTrPAC clinical centers. Both sites will generate IMAT and subcutaneous adipose
tissue conditioned media from fresh tissue, followed by conditioned media analyses and testing of its direct
metabolic effects in vitro in Colorado. IMAT will also be analyzed using single nuclei RNAseq to measure
cell composition. Specific Aim 2 – Evaluate the extent to which age and exercise training alter IMAT
secretion of myostatin, IMAT lymphocyte composition, and the potency of myostatin in the IMAT secretome
to promote sarcopenia in vitro. We hypothesize that the IMAT secretome promotes sarcopenia via
myostatin signaling that increases with age due to greater IMAT lymphocyte content and is attenuated after
exercise training. In vitro experiments will determine the degree to which IMAT myostatin secretion
explains IMAT-induced sarcopenia outcomes. The proposed research is innovative because it represents a
new and substantive departure from the status quo by testing specific IMAT secreted paracrine signals
rather than clinical associations with IMAT content. These contributions will be significant by identifying the
first IMAT paracrine signals impacting muscle insulin sensitivity and sarcopenia revealing IMAT as a novel
target to combat aging-induced sarcopenia and metabolic dysfunction.

Grant Number: 5R01AG077956-04
NIH Institute/Center: NIH
Principal Investigator: BRYAN BERGMAN