Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY/ABSTRACT Skeletal muscle shows amazing plasticity and has the capacity to continuously regulate its size in response to external cues such as mechanical load, neural activity, hormones, growth factors, and nutritional status. The maintenance of muscle mass is controlled by a balance between protein synthesis and protein degradation pathways, a balance that shifts toward protein degradation during atrophy and protein synthesis during hypertrophy. To date, protein synthesis and degradation systems have been extensively studied in the context of muscle growth and wasting, while work to identify and characterize novel modulators of muscle hypertrophy and atrophy has been less prolific. As an example, the MAP kinase signaling pathway has been found to play an array of roles in skeletal muscle ranging from the regulation of fiber type development to controlling protein synthesis and autophagy pathways. Interestingly, gene expression analysis of muscle tissue isolated from mice following denervation revealed that Dusp4, a known negative regulator of MAP kinase signaling, is significantly upregulated. Further, previous studies suggest that Dusp4 preferentially regulates the Erk1/2 branch of the MAP kinase signaling cascade in skeletal muscle. While Dusp4 is rapidly and robustly upregulated in response to sciatic nerve transection, the functional consequence of upregulation of this dual-specificity phosphatase during neurogenic skeletal muscle atrophy remains unclear. Therefore, the overall objective of this investigation is to characterize the functional role of Dusp4 in modulating the molecular mechanisms that regulate muscle size and strength and determine how Dusp4 contributes to changes in muscle mass. This objective will be accomplished through the completion of the following specific aims. In aim 1, we will determine if Dusp4 expression is necessary and sufficient to induce muscle atrophy using in vivo electroporation of skeletal muscle to knockdown or overexpress Dusp4 for 3- and 14-days followed by measurement of muscle weight, myofiber cross sectional area, fiber type composition, and expression levels of markers of protein synthesis and atrophy. We hypothesize that knockdown of Dusp4 in denervated muscles will attenuate muscle atrophy, while overexpression of Dusp4 will promote skeletal muscle wasting. In aim 2, we will explore the hypothesis that Dusp4-mediated dephosphorylation may serve as a signal to alter the activity, localization, and/or stability of putative substrates in muscle. This hypothesis will be tested using an in vivo overexpression approach combined with an unbiased phosphoproteomic analysis to identify and validate the full complement of Dusp4 targets in skeletal muscle. The successful completion of this project will demonstrate for the first time that Dusp4 acts as a regulator of skeletal muscle mass through modulation of the Erk1/2 branch of the MAP kinase signaling pathway. Furthermore, if the findings of this investigation demonstrate that Dusp4 participates in the neurogenic atrophy cascade by acting as a direct or indirect modulator of muscle wasting, then inhibition of this dual-specificity phosphatase could prove beneficial in the treatment of skeletal muscle atrophy associated with neuromuscular disorders, neurodegenerative diseases, and aging.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
