ABSTRACTMARCUS MICHAEL LAWRENCE. Glycogen Enhancement Augments Overload-Induced Protein Synthesis, Growth, and Myogenesis in Aged Skeletal Muscle. (Under the direction of DR. SCOTT E. GORDON)Age-related skeletal muscle (SkM) wasting is associated with elevated 5’-AMP-Activated Protein Kinase (AMPK) activity, which inhibits overload-induced (OI) SkM protein synthesis (MPS) and growth. Glycogen, an inhibitor of AMPK, is reduced in aged SkM. We performed a series of experiments to examine the effects of manipulating glycogen on AMPK, MPS and related signaling, and OI-growth in aged SkM. Mutant glycogen synthase (GS; designed to enhance SkM glycogen content [GC]) or empty-vector plasmids were electrotransferred into fast-twitch plantaris muscles prior to 21-day synergist ablation-induced unilateral overload in young adult (8 mo.; empty vector; YE) and old (33 mo.; empty vector, OE; or mutant GS, OM) male FBN rats. Contralateral limbs underwent SHAM ablations with no plasmid. There were significant increases in OI-(all vs. SHAM) MPS and hypertrophy in YE and OM groups only. As expected, mutant GS expression and GC were significantly higher in OM overloaded muscles (the only muscles receiving the mutant GS plasmid) vs. SHAM OM muscles or vs. both SHAM or overloaded YE and OE muscles. Markers of AMPK activity and other signaling intermediates affecting MPS were largely unaltered by glycogen enhancement. Subsequent experiments in which the mutant GS vs. empty-vector plasmid were transfected into cultured C2C12 skeletal muscle myotubes also confirmed a positive effect of enhanced GC on MPS with little change in underlying signaling intermediates affecting MPS. However, there was a strong and significant effect of enhancing GC (via mutant GS vs. empty vector plasmid) on myogenic regulatory factors, embryonic myosin heavy chain-positive fibers, and total fiber number in aged muscle under conditions of overload in vivo. Thus, enhancing GC may lead to enhanced MPS and OI growth in aged SkM. This effect may be due, in part, to an enhanced myogenesis.