Work in the laboratory of Dept of Cell Biology Professor Alfred Goldberg provides insight into mechanism of muscle atrophy.

Atrophy of skeletal muscle occurs upon disuse or denervation and systemically in fasting and many disease states, including cancer cachexia, sepsis, renal failure and cardiac failure. The mechanism for disassembly and degradation of myofibrillar components during atrophy has long been uncertain, and most prior investigators have concluded that the myofibril is initially attacked by calpains or caspases. However, in a paper published recently in Journal of Cell Biology (June 8, 2009), Shenhav Cohen et al suggest a critical role for the ubiquitin ligase MuRF1 in disassembly of the myofibril in atrophying muscles.  This E3 is dramatically induced during atrophy,  and its deletion attenuates muscle wasting,. They used biochemical and genetic approaches to show that certain regulatory proteins known to stabilize the thick filament (Myosin-binding protein C, and Myosin light chains 1 and 2) are lost selectively during atrophy by a MuRF1-dependent mechanism, and that these proteins can be ubiquitylated by MuRF1, while still in the myofibril. In mice lacking a functional MuRF1, these proteins are not lost and atrophy is reduced.  MuRF1 can also ubiquitylate the major myofibrillar components, Myosin Heavy Chain and Actin, when they are purified, but in the intact myofibril, these proteins are protected initially.  However, with time Myosin Heavy Chain is lost from the myofibril by a MuRF1-dependent mechanism but the loss of the thin filament components (i.e., Actin, Tropomyosin,-Actinin) do not require MuRF1. Their data thus suggest a novel sequential model for myofibrillar loss in atrophy, based upon initial selective ubiquitylation of the thick filament stabilizing proteins by MuRF1, followed by increased accessibility of Myosin Heavy Chain to MuRF1. Although MuRF1 is required for the degradation and disassembly of the thick filaments during denervation atrophy, the thin filaments are degraded by a distinct mechanism, which probably involves another ubiquitin ligase.

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Neil Ganem and Susana Godinho in David Pellman’s laboratory have uncovered what may be a common cause of chromosome instability.

Chromosome instability (CIN, increased rates of whole chromosome mis-segregation) is a common feature of many cancers. It has been known for a long time that centrosome amplification in cancer cells is correlated with CIN, but the reason has been unclear. One widely cited idea has been that centrosome amplification causes multipolar divisions, where cells fragment into three or more highly aneuploid daughter cells. In paper published in Nature Ganem et al. performed live cell imaging of thousands of divisions in CIN cancer cell lines with centrosome amplification and found that multipolar divisions almost never occur and when they do, the progeny are typically inviable. Instead, centrosome amplification leads to CIN because cancer cells pass though a transient multipolar state that is then resolved into a relatively normal appearing bipolar spindle. While passing though this transient multipolar state, cancer cells acquire abnormal, ‘merotelic’, kinetochore-microtubule attachments, where individual chromosomes are caught in a tug of war between microtubules from opposite spindle poles. The abnormally attached chromosomes lag behind their normally attached brethren and can then be mis-segregated. Thus geometry may play as important a role as genes in generating the chromosome instability observed in human cancers.