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

Abstract

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 disrupt normal bone remodeling and result in morbidity that includes muscle weakness. Tumor in bone stimulates excessive osteoclast activity, which causes the release of growth factors stored in the mineralized bone matrix. These factors fuel a feed-forward vicious cycle of tumor growth in bone and bone destruction. Recent evidence indicates that these bone-derived growth factors can act systemically to cause muscle weakness. Muscle weakness can be caused by reduced muscle mass or reduced muscle function; in advanced disease, it is likely due to a combination of both reduced quantity and quality of muscle. In this review, we discuss possible mechanisms that lead to skeletal muscle weakness due to bone metastases.

Bone Pain and Muscle Weakness in Cancer Patients

“…Cancer-related muscle loss is multifactorial, resulting in asthenia and functional impairment similar to that seen in patients with age-related sarcopenia as well that manifested by active muscle break-down. [87, 88] The common metabolic abnormalities to cancer cachexia and sarcopenia include altered hormone levels, elevated cytokines, increased insulin resistance, increased muscle proteolysis, elevated acute phase proteins, and altered nutrient utilization. [87] Many experts believe, however, that muscle loss in cancer is a more active process, mediated by a number of pro-inflammatory cytokines, as well as members of the TGFβ-superfamily including activins[89] and myostatin.…”

“…[87] Bone and muscle function are interdependent physiologically. However, in cancer patients, accelerated bone resorption due to metastases increases “osteokines,” which significantly alter muscle function.…”

“…Similarly, factors released from muscle can further exacerbate bone’s role in muscle dysfunction. [87] Normal excitation-contraction (E-C) coupling in skeletal muscle involves release of sequestered calcium from the sarcoplasmic reticulum into the cytoplasm via the activated ryanodine receptor/calcium release channel (RyR1), leading to calcium-dependent actin-myosin cross-bridging and muscle contraction. [108] Modifications to RyR1 from chronic oxidative stress causes disruption of RyR1 and its stabilizing subunit calstabim1, resulting in leaky calcium channels.…”

“…In addition, TGFβ, a critical bone remodeling factor can mediate oxidative stress, and thereby further contribute to muscle dysfunction. [87]…”

Bone mineral density and content are differentially impacted by aerobic and resistance training in the colon-26 mouse model of cancer cachexia

“…Given that several signaling events are common to both muscle and bone, inter-organ cross-talk and concurrent degeneration of bone in cancer cachexia is not surprising [8][9][10]. It was recently reported that metastasized bone contributes to cachexia-associated skeletal muscle dysfunction [11], suggesting regulation of skeletal muscle by bone.…”