All ETDs from UAB

Advisory Committee Chair

Matthew Alexander

Advisory Committee Members

Marcas Bamman

Thomas Buford

Zachary A Graham

Merry-Lynn N McDonald

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Sarcopenia is a decrease in skeletal muscle (SKM) mass occurring with age. This disease is natural, so it is important to increase SKM mass to counteract. This need is seen in diseases leading to muscle atrophy (i.e., insulin resistance and diabetes). The most efficient way to promote SKM hypertrophy is resistance exercise training (RT), however there is high response heterogeneity. To investigate SKM heterogeneity and maximizing SKM hypertrophy, we conducted a double-blind two-site placebo controlled clinical trial: “Metformin to Augment Strength Training Effective Response in Seniors (MASTERS)”. Here participants > 65 years underwent RT for 14 weeks. Measurements of SKM mass and SKM samples were obtained. For this dissertation, we used placebo participants from MASTERS to investigate molecular and cellular mechanisms of RT-induced SKM hypertrophy heterogeneity in older adults. For study one, we used RNA from baseline SKM to perform transcriptomewide poly-A RNA sequencing (n=31) investigating transcriptional networks linked to RT-induced SKM hypertrophy measured by mid-thigh CSA. Networks were classified as predictive, responsive, or plastic. Prediction analysis confirmed genes related to training adaptions and uncovered novel genes that could be used for research understanding the baseline gene expression profile responsible for SKM hypertrophy. Responsive networks revealed an increase in genes of aerobic metabolism and decrease in spliceosome and iv type-1 myofiber genes. There were no significant gene groups from the plasticity analysis. This suggests baseline gene expression contributes more to heterogeneity than RT-induced changes. For the second study, we used myoblast from participants of MASTERS (n=10) to investigate if the magnitude of SKM hypertrophy observed in older adults after RT is recapitulated in vitro. Myoblast were differentiated into myotubes and markers of myogenesis, ribosome biogenesis, and protein synthesis were measured after FBSinduced hypertrophy. High responders showed better myotube formation than low responders in vivo. However, there were no significant group-by-treatment interactions with markers of interest. This suggest differences between low and high SKM hypertrophy may be more influenced by the in vivo muscle environment than differences in myogenic cells proper. Taken together, these studies provide great insight to cellular and molecular mechanisms responsible for RT-induced SKM response heterogeneity in older adults.

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