Abstract
BackgroundSkeletal muscle atrophy is a pathological condition that contributes to morbidity in a variety of conditions including denervation, cachexia, and aging. Muscle atrophy is characterized as decreased muscle fiber cross-sectional area and protein content due, in part, to the proteolytic activities of two muscle-specific E3 ubiquitin ligases: muscle RING-finger 1 (MuRF1) and muscle atrophy F-box (MAFbx or Atrogin-1). The nuclear factor-kappa B (NF-κB) pathway has emerged as a critical signaling network in skeletal muscle atrophy and has become a prime therapeutic target for the treatment of muscle diseases. Unfortunately, none of the NF-κB targeting drugs are currently being used to treat these diseases, likely because of our limited knowledge and specificity, for muscle biology and disease. The cellular inhibitor of apoptosis 1 (cIAP1) protein is a positive regulator of tumor necrosis factor alpha (TNFα)-mediated classical NF-κB signaling, and cIAP1 loss has been shown to enhance muscle regeneration during acute and chronic injury.MethodsSciatic nerve transection in wild-type, cIAP1-null and Smac mimetic compound (SMC)-treated mice was performed to investigate the role of cIAP1 in denervation-induced atrophy. Genetic in vitro models of C2C12 myoblasts and primary myoblasts were also used to examine the role of classical NF-κB activity in cIAP1-induced myotube atrophy.ResultsWe found that cIAP1 expression was upregulated in denervated muscles compared to non-denervated controls 14 days after denervation. Genetic and pharmacological loss of cIAP1 attenuated denervation-induced muscle atrophy and overexpression of cIAP1 in myotubes was sufficient to induce atrophy. The induction of myotube atrophy by cIAP1 was attenuated when the classical NF-κB signaling pathway was inhibited.ConclusionsThese results demonstrate the cIAP1 is an important mediator of NF-κB/MuRF1 signaling in skeletal muscle atrophy and is a promising therapeutic target for muscle wasting diseases.
Highlights
Skeletal muscle atrophy is a pathological condition that contributes to morbidity in a variety of conditions including denervation, cachexia, and aging
Since cellular inhibitor of apoptosis 1 (cIAP1) is a critical positive regulator of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling in the skeletal muscle [22,23,24] and since cIAP1 is upregulated in the denervated muscle, we examined whether NF-κB signaling could be mediating cIAP1-induced atrophy
We demonstrate that in the absence of cIAP1, muscle really interesting new gene (RING)-finger 1 (MuRF1) consistently fails to be upregulated in denervated muscle, suggesting that one of the mechanisms by which loss of cIAP1 inhibits the degradation of muscle protein and confers protection against denervation-induced skeletal muscle atrophy is through blocking activation of the ubiquitin-proteasome system (UPS)
Summary
Skeletal muscle atrophy is a pathological condition that contributes to morbidity in a variety of conditions including denervation, cachexia, and aging. Muscle atrophy is the outcome of adaptive and pathological circumstances, in which anabolic processes that promote synthesis are counterbalanced by (2019) 9:13 or Atrogin-1) [3, 4], allowed the study of atrophy as an outcome of signal transduction events that could be pharmacologically manipulated for therapeutic purposes These ubiquitin ligases are regulated by a number of cellular signaling pathways including those involving nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factors [5, 6]. Due to its importance in muscle pathology, the NF-κB signaling pathway is a therapeutic target for a variety of diseases and, numerous inhibitors have been evaluated in human trials [11, 12] None of these drugs are currently being used to treat skeletal muscle atrophy, likely because our ability to target NF-κB in muscle is hampered by our limited understanding of its complex regulation
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