Cancer-associated muscle weakness: What’s bone got to do with it?

Cancer-associated muscle weakness is an important paraneoplastic syndrome for which there is currently no treatment. Tumor cells commonly metastasize to bone in advanced cancer to Metastasizing tumor cells mobilize and sculpt the bone microenvironment to enhance tumor growth and to promote bone invasion.

Understanding the crucial components of the bone microenvironment that influence tumor localization, along with the tumor-derived

factors that modulate cellular and protein matrix components of bone to favor tumor expansion and invasion, is central to the pathophysiology of bone metastases.

Tumor invasion into bone is associated with osteoclast and osteoblast recruitment, resulting in the liberation of growth factors from the bone matrix, which can feed back to enhance tumor growth resulting in the ‘vicious cycle’ of bone metastases.

Tumor in bone stimulates excessive osteoclast activity, which causes the release of growth factors stored in the mineralized bone matrix. Recent evidence indicates that these bone-derived growth factors can act systemically to cause muscle weakness.

TGFβ plays a central role in tumor growth in the bone and is released in high concentrations from the mineralized bone matrix during osteoclastic bone resorption. Our recent work has shown that TGFβ leads to significant skeletal muscle weakness in mice with osteolytic ca

ncer in the bone. This occurs through NADPH oxidase 4 (Nox4) mediated ryanodine receptor (RyR1) oxidation that causes RyR1 Ca²⁺ leak and weakness. We have targeted multiple points in the TGFβ-Nox4-RyR1 axis to therapeutically improve muscle weakness.

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Cancer cachexia

A significant co-morbidity of bone metastases is often cachexia. Cachexia is a common paraneoplastic syndrome that is characterized by severe wasting due to loss of skeletal muscle mass (with or without loss of fat mass) due to a negative protein balance caused by abnormal metabolism. Cancer cachexia is a multifactorial syndrome that is common in advanced malignancy occurring in ∼80% of patients, which cannot be reversed by nutritional support and leads to significant function deficits and is estimated to be responsible for 20% of cancer-related deaths. However, there is a large heterogeneity in clinical presentation of cachexia that can vary according to tumor type, site and individual patient factors. Reducing cachexia has been shown to extend life span even without affecting tumor growth in mice. Improving muscle function and mobility of cancer patients should thus have a positive impact on adherence to treatment regimens and overall health.

Activin plays a central role in skeletal muscle atrophy and cachexia and along with TGFβ, is released in high concentrations from the mineralized bone matrix during osteoclastic bone resorption. The high-affinity activin receptor type 2B, ActRIIB, mediates signaling of a small group of TGFβ family members, including activin, myostatin and GDF-11, and is important in regulating muscle mass.

Pharmacological blockade of ActRIIB prevents muscle wasting, induces muscle satellite cell mobilization and differentiation and significantly prolongs survival in murine models of cachexia. It is likely that these proteins promote the muscle wasting characteristic of cachexia, whereas other mediators contribute to muscle dysfunction by altering calcium handling (e.g. RyR1) or myofibrillar proteins in muscle cells.

Our recent work with activin inhibition in mice with osteolytic cancer in bone and skeletal muscle wasting and weakness shows a potential therapeutic target for this devestating consequence of advanced cancer and cancer therapy.