Year: 2024
Type: conference-abstract
Abstract: Cachexia or muscle wasting is common in metastatic disease and is associated with poor quality of life and is the number one cause of morbidity in patients with advanced malignancies. There are no effective treatments available for this debilitating syndrome. Therefore, the identification of novel therapeutic avenues to target cachexia is of utmost importance in the management of muscle wasting. Most proteins work in a compartmentalization manner and mislocalization of proteins to the incorrect cellular compartment causes their functional inactivation and is linked to several pathologies. Muscle wasting related proteins and their regulators continuously shuttle between the nucleus and cytoplasm. However, to date, the role of protein transport has not been investigated in cachexia. Although we have significant insights on the role of atrogin-1 and MuRF1 and their activation during cachexia, there are no studies that have investigated their nuclear-cytoplasmic regulation. This is significant since atrogin-1 is regulated by several nuclear cytoplasmic shuttling proteins such as Forkhead box O (FoxO) and NF-kB. Aberrant nuclear transport, particularly the hyper-activation of major nuclear exporter protein Exportin 1 (XPO1) is commonly seen in advanced cancers. Such hyper transport activity may cause persistent nuclear expulsion of cachexia suppressors that in principle could impact muscle wasting pathways. In this study we evaluated the role of XPO1 in cachexia or muscle wasting. Cachexia models were generated by treating differentiated C2C12 cells with dexamethasone. Treatment of differentiated myotubes with dexamethasone caused a significant decrease in myotube diameter. Most interestingly, we observed statistically significant prevention of dexamethasone induced myotube atrophy (increased myotube diameter) when XPO1 inhibitor selinexor was given with dexamethasone concurrently. These results show that at sub-toxic doses XPO1 inhibitor can possibly prevent chemically induced myotube atrophy. Additionally, treatment with selinexor caused inhibition of atrogin-1 and FOXO protein levels in these C2C12 cachexia models. siRNA silencing of XPO1 also resulted in statistically significant reduction in the expression of atrogin-1 and MuRF1 mRNA levels in C2C12 muscle cells. Mechanistic studies on the major proteins responsible for muscle atrophy preventing effect of XPO1 inhibitor are ongoing. In conclusion, our findings for the first time highlight the previously not recognized role of nuclear transport in muscle wasting that warrant further clinical investigations.
Source: Journal of Biological Chemistry
Authors: Irfana Muqbil, Dingqiang Zhang, Asfar Azmi
Institution: Lawrence Technological University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,800
Funder: New York Institute of Technology
OpenAlex ID: W4393139354