UC San Diego

Time-of-day has been shown to regulate exercise capacity, with skeletal muscle function proposed to be the key regulator. Skeletal muscle plays a central role in exercise performance and systemic energy metabolism, serving as the primary site of post-prandial glucose disposal. However, as of this dissertation, no study has empirically tested intrinsic muscle function at different times-of-day. Further, the mechanisms by which skeletal muscle takes up glucose from the blood in response to contractions remain to be fully defined. We focused on the lysine acetyltransferases E1A binding protein p300 (p300) and cAMP response element binding protein binding protein (CBP) as potential regulators of contraction-stimulated (C-stim) glucose uptake because they have previously been shown to be required for insulin-stimulated glucose uptake and their activity can be regulated by various C-stim kinases. Thus, the objective of this dissertation was to determine if the intrinsic physiological properties of skeletal muscle are regulated by time-of-day and to investigate the role of p300/CBP in C-stim glucose uptake. To measure the intrinsic physiological properties of skeletal muscle, we used an ex vivo approach to control for neuromuscular interactions, temperature, and substrate availability. In Study #1, we found that time-of-day does not regulate the intrinsic contractile properties of skeletal muscle, including submaximal and maximal force production, endurance, or ability to take up glucose from the blood in response to contractions. In Study #2, we found that time-of-day does not regulate mitochondrial function at the transcript, protein, or enzymatic level in skeletal muscle. In Study #3, we demonstrate that p300 and CBP are essential for C-stim glucose uptake using both inducible, skeletal muscle-specific knockouts of p300/CBP and pharmacologic inhibitors of p300/CBP acetyltransferase activity. In summary, we demonstrate that while time-of-day does not regulate intrinsic skeletal muscle contractile function, mitochondrial function, or C-stim glucose uptake, p300/CBP are required for C-stim glucose uptake and are potentially novel fundamental regulators of C-stim glucose uptake.