Cancer cachexia is regulated by selective targeting of skeletal muscle gene products
Swarnali Acharyya, … , Steven Swoap, Denis C. Guttridge
Swarnali Acharyya, … , Steven Swoap, Denis C. Guttridge
Published August 1, 2004
Citation Information: J Clin Invest. 2004;114(3):370-378. https://doi.org/10.1172/JCI20174.
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Article Oncology

Cancer cachexia is regulated by selective targeting of skeletal muscle gene products

Abstract

Cachexia is a syndrome characterized by wasting of skeletal muscle and contributes to nearly one-third of all cancer deaths. Cytokines and tumor factors mediate wasting by suppressing muscle gene products, but exactly which products are targeted by these cachectic factors is not well understood. Because of their functional relevance to muscle architecture, such targets are presumed to represent myofibrillar proteins, but whether these proteins are regulated in a general or a selective manner is also unclear. Here we demonstrate, using in vitro and in vivo models of muscle wasting, that cachectic factors are remarkably selective in targeting myosin heavy chain. In myotubes and mouse muscles, TNF-α plus IFN-γ strongly reduced myosin expression through an RNA-dependent mechanism. Likewise, colon-26 tumors in mice caused the selective reduction of this myofibrillar protein, and this reduction correlated with wasting. Under these conditions, however, loss of myosin was associated with the ubiquitin-dependent proteasome pathway, which suggests that mechanisms used to regulate the expression of muscle proteins may be cachectic factor specific. These results shed new light on cancer cachexia by revealing that wasting does not result from a general downregulation of muscle proteins but rather is highly selective as to which proteins are targeted during the wasting state.

Authors

Swarnali Acharyya, Katherine J. Ladner, Lori L. Nelsen, Jeffrey Damrauer, Peter J. Reiser, Steven Swoap, Denis C. Guttridge

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Figure 1

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MyHC is selectively targeted by TNF/IFN signaling. C2C12 myoblasts were ...
MyHC is selectively targeted by TNF/IFN signaling. C2C12 myoblasts were differentiated in DM for 3 days and subsequently switched to medium alone or containing TNF (10 ng/ml) and IFN (100 U/ml) for 48 hours. (A) Immunofluorescence to detect expression of myofibrillar proteins (MyHC, fast twitch; troponin T [Tn]; tropomyosin, α and β [TM]; actin, α skeletal). Images are shown at ×20 magnification. (B) Immunostained expression levels of myofibrillar proteins were quantitated using Zeiss AxioVision software (Carl Zeiss Inc., Thornwood, New York, USA). The data were calculated from a minimum of ten randomly chosen fields of cells at ×4 magnification. (C) Whole-cell extracts were prepared from untreated or TNF/IFN–treated myocytes, and 50 μg total protein was used in Western analyses to probe for myofibrillar proteins (troponin; α- and β-tropomyosin; MyLC, myosin light chain). (D) Immunofluorescence of untreated (black bars) or TNF/IFN–treated (hatched bars) C2C12 myotubes, probing for MyHC (Ab1, MyHC antibody MY-32; Ab2, MyHC antibody MF20). (E) Primary myotubes were either untreated (black bars) or treated with TNF and IFN (hatched bars) for 48 hours. Cells were stained by immunofluorescence for myofibrillar proteins, and the level of protein expression was quantitated by digital capture and AxioVision software. For histograms, each bar represents mean ± SEM from three independent experiments.