Project Summary Loss of muscle mass, as seen in cancer cachexia, and sarcopenia correlates with heightened mortality rates, making it a global health concern with the aging population. We desperately need advanced molecular understanding to develop effective therapies. The intricate regulation of muscle mass involves several signaling pathways, orchestrating gene expression changes via activation and repression of transcription factors activity. Recent findings from our lab have uncovered the role for the transcription factor Maf in the maturation of fast twitch myofibers by directly activating fast muscle gene expression. Fast twitch myofibers are more affected than slow twitch myofibers in numerous atrophic conditions. Interestingly, Maf expression and activity are repressed during muscle atrophy. Our preliminary data indicate that Maf overexpression can suppress muscle atrophy. We hypothesize that Maf functions as a transcriptional repressor of the atrophic gene program, offering a promising therapeutic avenue. This proposal outlines a comprehensive plan to dissect the functions of Maf during muscle atrophy. To accomplish this, I will employ the following specific Aims: 1. To examine the transcriptional role of Maf in skeletal muscle atrophy. 2. To identify the partners and regulators of Maf activity in skeletal muscle. 3. To investigate the protective role of Maf in cachexia and sarcopenia. The K99 portion of this proposal will be carried out in the lab of the renowned molecular biologist, Dr. Eric Olson. In order to gain research independence through mentored training, I will continue to develop expertise in applying transcriptome profiling, including single nuclei RNAseq, to study how Maf transcriptionally reprograms myofibers (Aims 1). The proposed research also requires that I acquire additional mentoring to evaluate the partners of Maf using proteomic mass spectrometry, and the AAV gene therapy detailed in Aim 2 and 3. The knowledge and skills that I acquire during this time will serve as critical components of the foundation of my own independent lab. In summary, the structured approach detailed in this Pathway to Independence Award application not only promises to advance my growth as an independent researcher but also intends to make significant contributions to neuromuscular research. The anticipated outcomes from the proposed aims have the potential to reshape the understanding of muscle atrophy and lay the groundwork for my scientific journey.