Almost one-third of cancer deaths are due to cachexia — a wasting condition characterized by loss of skeletal muscle — and not due to tumour burden. Although we know some key cachetic factors — such as the cytokines tumour necrosis factor-α (TNFα), interferon-γ (IFNγ) and interleukin-6 (IL6) — their targets within muscle have not been identified. Denis Guttridge and colleagues now report that cachetic factors selectively target the myosin heavy chain (MYHC), and find that the mechanism by which they reduce myosin expression is factor-dependent.

The authors studied the effect of TNFα in combination with IFNγ on the expression of myofibrillar proteins in a mouse myotube culture model and in primary mouse myotubes. Only expression of MYHC — which accounts for about 40% of myofibrillar protein in muscle — was decreased. Although TNFα or IFNγ alone had little effect, together they reduced mRNA levels of both Myhc and the myocyte regulatory factor Myod , which controls transcriptional activation of a key isoform of MYHC. Exogenous expression of MYOD rescued Myhc transcription in the presence of TNFα and IFNγ, indicating that the cytokines act by inhibiting MYOD synthesis. MYHC protein turnover was not altered in the myotube models. Analysis of the effects of TNFα plus IFNγ in vivo, using cytokine-expressing and control chinese hamster ovary cells injected intramuscularly into mice, confirmed the selective decrease in Myhc mRNA.

So, does this mechanism of reduction of muscle protein hold true in the context of cancer? To assess this, Guttridge and colleagues examined MYHC in an established cancer cachexia model — the colon-26 adenocarcinoma mouse. Although this model is dependent on IL6 rather than TNFα or IFNγ, the authors reasoned that MYHC would be a selective target no matter which factor induced the cachexia, and they did indeed show selective reduction of MYHC. However, interestingly, Myhc mRNA levels were not reduced in the cachetic muscles. Instead, they found that reduction occurred at the protein level. Expression of the degradation-targeting protein ubiquitin, together with muscle-specific ubiquitin-pathway genes, was increased in cachetic muscles. In addition, immunoprecipitation studies showed that MYHC fragments were present in the cachetic muscles, and in some muscles less myosin was co-precipitated with ubiquitin, indicating that the myosin in these muscles had already been degraded.

MYHC is therefore the main target of many cachetic factors, but the mechanism of myosin loss varies and might be factor-specific. The authors also showed that loss of myosin leads to reduced complexes of myosin with its main binding partner, sarcomeric actin, but the downstream consequence of myosin loss needs to be investigated further.