CELLULAR ENERGETICS AS A REGULATOR OF MUSCLE MASS AND MITOCHONDRIAL CONTENT DURING MUSCLE ATROPHY

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Project Summary Skeletal muscle atrophy is a major cause of disability and death in many chronic diseases, e.g. cancer, diabe- tes, and heart failure. Despite diverse etiology, atrophying muscles share many common features, like loss of mitochondrial content and depressed energetic state. One probable regulator of muscle mass and mitochon- dria during atrophy is the metabolic enzyme AMP deaminase (AMPD), which isoform 3 is increased up to 100- fold during atrophy. AMPD catalyzes the thermodynamically irreversible degradation of AMP and thereby also controls the size of the adenine nucleotide (ATP ↔ ADP ↔ AMP) pool. Binding or degrading AMP is particu- larly important since its free, cytosolic levels are detected by the energy sensing enzyme AMP-activated pro- tein kinase (AMPK), a well-described inducer of mitochondrial content. Thus, AMPD3 is uniquely positioned to modulate a major intracellular energetic signal, [AMP]/[ATP] ratio. To date, the molecular mechanisms that link muscle atrophy, cellular energetics, and mitochondria biogenesis are largely unknown. The long-term goal of this project is to identify new targets to increase muscle mass, mitochondrial content and perhaps improve the energetic state and function of atrophic muscle. The objective of this application is to determine whether during muscle atrophy AMPD3 decreases mitochondrial production and accelerates muscle protein loss. The central hypothesis is that high levels of AMPD3, which degrades the adenine nucleotide pool, triggers loss of mito- chondria and increases the rate of protein degradation. This is based, in part, on exciting preliminary data from cultured muscle showing that overexpression of AMPD3 mimics the energy deficit of atrophy, increases prote- olysis rate, and decreases protein content; while knockdown of AMDP3 in adult muscle protects against mus- cle weight loss of denervation atrophy. To test the central hypothesis, we propose to knockdown or remove AMPD3 in skeletal muscle fibers/cells that are non-atrophying or atrophying due to various energetic insults: either surgical denervation of one hindlimb (decreased energy demand), food deprivation (decreased energy supply), and glucocorticoid treatment (increase in demand and decrease in supply). The Aims of this proposal are to 1) To determine the role of AMP deaminase as a mediator of mitochondrial loss during skeletal muscle atrophy, and 2) determine the role of AMP deaminase as a mediator of protein loss during skeletal muscle at- rophy. The working hypotheses are that loss of AMPD3 during atrophy will increase [AMP], mitochondrial bio- genesis, and mitochondrial content. Conversely, overexpression of AMPD3, because of impairment in cellular energetics, will trigger accelerated protein degradation and muscle fiber size loss. The expected results of this proposal, demonstrating the energetic control of muscle atrophy, will not only provide novel insights into how energetics/metabolism and muscle mass are linked mechanistically, but will also be expected to reveal novel therapeutic targets to slow or stop muscle mass loss in most, if not all, atrophy conditions.