Disease relevance of FBXO32

• Atrogin-1 and MuRF1 increased after the hypertrophy and decreased after the atrophy phases [1].
• Therefore, here we have shown that FBXO25 is a novel F-box protein analogous to atrogin-1, which is not involved in muscle atrophy [2].
• In cardiac hypertrophy, Atrogin1 and MuRF1 attenuate cardiac hypertrophy by interacting with calcineurin and PKCepsilon, respectively [3].
• Additionally, peritonitis produced by cecal ligation and puncture increased atrogin-1 and MuRF1 mRNA in gastrocnemius (but not soleus or heart) by 8 h, which was sustained for 72 and 24 h, respectively [4].
• The major advance in the field has been: (i) the discovery of the atrogin-1 gene and (ii) the application of microarray expression analysis and proteomics with the objectives of obtaining comprehensive understanding of the pathways changed with disuse atrophy [5].

High impact information on FBXO32

• This perspective will focus on the signalling pathways that control skeletal muscle atrophy and hypertrophy, including the recently identified ubiquitin ligases muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx), as a basis to develop targets for pharmacologic intervention in muscle disease [6].
• Transfection of PGC-1alpha into adult fibers reduced the capacity of FoxO3 to cause fiber atrophy and to bind to and transcribe from the atrogin-1 promoter [7].
• Muscle atrophy after 4 d of high-dose dexamethasone was associated with increased mRNA of enzymes involved in proteolytic pathways (atrogin-1, muscle ring finger 1, and cathepsin L) and increased chymotrypsin-like proteasomal activity [8].
• The expression of MAFbx/Murf-1 and troponin I was analyzed by RT-PCR and Western blotting in the non-infarcted area of the left ventricle [9].
• Our results showed that, despite the presence of TNF-alpha/IFN-gamma, IGF-I retained its full ability to induce the phosphorylation of Akt, Foxo3a, and GSK-3beta (respectively, 16-fold, 9-fold, and 2-fold) together with a decrease in atrogin-1 mRNA (-39%, P < 0.001) [10].

Biological context of FBXO32

• IGF-I rapidly reduced atrogin-1 expression within 1 h by blocking mRNA synthesis without affecting mRNA degradation, whereas IGF-I decreased MuRF1 mRNA slowly [11].
• Subjects underwent a percutaneous muscle biopsy of the vastus lateralis to determine: (1) ubiquitin ligase gene expression (MAFbx and MuRF1); (2) frequency of apoptosis; and (3) individual fiber type and cross-sectional area [12].
• Atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 are associated with uterine smooth muscle involution in the postpartum period [13].
• The findings indicate an important role for the immediate upstream promotor of the human MAFbx gene in mediating its developmental expression and tissue specificity [14].
• This study evaluated the effect of ES based on chronaxie and rheobase on the expression of the myoD and atrogin-1 genes in denervated tibialis anterior (TA) muscle of Wistar rats [15].

Anatomical context of FBXO32

• In myotubes, dexamethasone (Dex) inhibited growth and enhanced breakdown of long-lived cell proteins, especially myofibrillar proteins (as measured by 3-methylhistidine release), while also increasing atrogin-1 and MuRF1 mRNA [11].
• Here we show that atrogin-1 is also expressed in smooth muscle, and that both atrogin-1 and MuRF-1 are upregulated in the uterus following delivery, as rapid involution occurs [13].
• A biopsy was obtained from the sternohyoid muscle in patients undergoing surgery for primary HPT (n=8) and in normocalcemic control patients undergoing thyroid surgery (n=11). mRNA levels for atrogin-1, MuRF1 and the calcium-regulated proteases, mu- and m-calpain, were determined by real-time PCR [16].
• To gain insights into mechanisms by which the human MAFbx gene is controlled, the structure of its upstream promotor were studied, and its expression in cultured cells was characterized [14].

Associations of FBXO32 with chemical compounds

• We investigated the differential expression of atrogin-1 and FBXO25 in fasted and dexamethasone-treated mice and also in rats with streptozotocin-induced diabetes [2].
• Changes in overall proteolysis with Dex and IGF-I correlated tightly with changes in atrogin-1 mRNA content, but not with changes in MuRF1 mRNA [11].
• Insulin and insulin-like growth factor-1 act through the phosphoinositide 3-kinase/AKT pathway to suppress the expression of two of these enzymes, MuRF1 and MAFbx/atrogin-1 [17].
• Finally, administration of the glucocorticoid receptor antagonist RU-486 did not prevent burn-induced atrophy of the gastrocnemius or the associated elevation in atrogin-1, MuRF-1, or polyUb [18].
• The aim of this study was to examine the effect of polyethylene glycol linked to soluble TNFRI (PEG-sTNFRI) on gene expression of the atrogens MuRF-1 and MAFbx in skeletal muscle of arthritic rats [19].

Regulatory relationships of FBXO32

• Gene knockdown of Oct-1 blocked repression of MAFbx reporter gene activity by testosterone and binding of AR to sequences conferring repression [20].

Other interactions of FBXO32

• Further work has demonstrated a trigger for MAFbx expression upon treatment with TNFalpha--the p38 MAPK pathway [21].
• Rates of skeletal muscle protein synthesis and breakdown, mRNA expression of IGF-I, myostatin, or the ubiquitin ligase muscle atrophy F-box protein (MAFbx) did not differ from basal during the 10-month asymptomatic period of infection [22].
• IGF-I does not prevent myotube atrophy caused by proinflammatory cytokines despite activation of Akt/Foxo and GSK-3beta pathways and inhibition of atrogin-1 mRNA [10].
• In addition, we measured transcript levels of genes known to regulate skeletal muscle atrophy, all of which are negatively regulated by IGF-1 (Mafbx/Atrogin-1, MuRF-1) [23].
• Atrophy in striated muscle results from enhanced protein breakdown and is associated with a common transcriptional profile and activation of the ubiquitin-proteasome pathway, including induction of the muscle-specific ubiquitin protein ligases atrogin-1 and muscle ring-finger protein 1 (MuRF-1) [13].

Analytical, diagnostic and therapeutic context of FBXO32

• Using a RT-PCR, we demonstrated that FBXO25 is highly expressed in brain, kidney, and intestine, whereas atrogin-1 expression is largely restricted to striate muscle [2].
• After 48 h of burn injury (40% total body surface area full-thickness scald burn) gastrocnemius weight was reduced, and this change was associated with an increased mRNA abundance for atrogin-1 and MuRF-1 (3.1- to 8-fold, respectively) [18].
• Furthermore, in transgenic mice overexpressing PGC-1alpha, denervation and fasting caused a much smaller decrease in muscle fiber diameter and a smaller induction of atrogin-1 and MuRF-1 than in control mice [7].
• In cell culture experiments the potency of TNF-alpha to stimulate Murf-1/MAFbx expression, the intracellular signaling pathway, and the involvement of the E3-ligases for the impairment of contractility were assessed [9].
• A real-time reverse transcription-polymerase chain reaction system showed that bedrest significantly upregulated expression of two ubiquitin ligase genes, Cbl-b and atrogin-1 [24].

References