Key result
Dusp29 is induced during neurogenic skeletal muscle atrophy, attenuates ERK1/2 signaling, destabilizes AMPK, and impairs glucocorticoid receptor transcriptional activity in muscle cells.
Why the study?
Dual-specificity phosphatase 29 (Dusp29) was newly identified as a novel neurogenic atrophy-induced gene, but how it is transcriptionally regulated and functions in skeletal muscle was unknown.
Dusp29 is identified as a novel neurogenic atrophy-induced gene that modulates key signaling pathways and glucocorticoid receptor activity in skeletal muscle cells, offering new mechanistic insights into muscle atrophy.
Dusp29 modulation may influence neurogenic atrophy but should not change practice; leaves open its validation as a therapeutic target in preclinical models.
Skeletal muscle atrophy is caused by a decrease in muscle size and strength and results from a range of physiological conditions, including denervation, immobilization, corticosteroid exposure and aging. Newly named dual-specificity phosphatase 29 ( Dusp29) has been identified as a novel neurogenic atrophy-induced gene in skeletal muscle. Quantitative PCR analysis revealed that Dusp29 expression is significantly higher in differentiated myotubes compared with proliferating myoblasts. To determine how Dusp29 is transcriptionally regulated in skeletal muscle, fragments of the promoter region of Dusp29 were cloned, fused to a reporter gene, and found to be highly inducible in response to ectopic expression of the myogenic regulatory factors (MRF), MyoD and myogenin. Furthermore, site-directed mutagenesis of conserved E-box elements within the proximal promoter of Dusp29 rendered a Dusp29 reporter gene unresponsive to MRF overexpression. Dusp29, an atypical Dusp also known as Dupd1/Dusp27, was found to attenuate the ERK1/2 branch of the MAP kinase signaling pathway in muscle cells and inhibit muscle cell differentiation when ectopically expressed in proliferating myoblasts. Interestingly, Dusp29 was also found to destabilize AMPK protein while simultaneously enriching the phosphorylated pool of AMPK in muscle cells. Additionally, Dusp29 overexpression resulted in a significant increase in the glucocorticoid receptor (GR) protein and elevation in GR phosphorylation. Finally, Dusp29 was found to significantly impair the ability of the glucocorticoid receptor to function as a transcriptional activator in muscle cells treated with dexamethasone. Identifying and characterizing the function of Dusp29 in muscle provides novel insights into the molecular and cellular mechanisms for skeletal muscle atrophy.
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Cooper et al. (2020) studied Skeletal muscle atrophy. Dusp29 ectopic expression was evaluated on Cellular signaling and transcriptional activity (ERK1/2, AMPK, GR). Dusp29 is induced during neurogenic skeletal muscle atrophy, attenuates ERK1/2 signaling, destabilizes AMPK, and impairs glucocorticoid receptor transcriptional activity in muscle cells.
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