Activin-β_Cmodulates cachexia by repressing the ubiquitin-proteasome and autophagic degradation pathways

Abstract

BackgroundCancer-associated cachexia and muscle wasting are considered key determinants of cancer-related death and reduction in the quality of life of cancer patients. A crucial link has been established between activin signaling and skeletal muscle atrophy-hypertrophy.We previously showed that activin-βC, a novel activin-A antagonist, is a tumor modulator that abolishes the cancer-associated cachexia in a mouse genetic model of gonadal tumorigenesis, in which the normal balance of inhibin/activin signalling is disrupted by a targeted mutation in the Inha gene (inhibin α-KO mouse). This study aimed to identify the molecular mechanism by which activin-βC increases survival and abolishes cancer-associated cachexia in α-KO mice. We hypothesized that overexpression of activin-βC modulates the cachexia phenotype by antagonizing the activin signaling pathway and repressing muscle wasting via the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways.MethodsMale and female ActC++, α-KO, and α-KO/ActC++ mice and WT littermate controls were studied. Western blot analysis for the specific E3 ubiquitin ligases, atrogin-1 and MuRF1, markers of the autophagic-lysosomal pathway, Beclin-1, p62, and LC3A/B, effectors Smad-2, Smad-3 and myostatin was performed in the gastrocnemius of age-matched mice. Histopathology of the gastrocnemius and survival analysis were also conducted in animals from the same breeding cohort. Serum levels of activin-A, inflammatory cytokines, hormonal profile, and bone density were also assessed.ResultsIncreased levels of atrogin-1, MuRF-1, Beclin-1, p62, LC3A/B-I, Smad-2 and serum levels of activin-A were noted in the α-KO mice. These mice developed gonadal cancers followed by severe weight loss, and reduced survival. Overexpression of activin- βC antagonized the activin signaling cascade, attenuating the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways, and reduced serum levels of activin-A. α-KO/ActC++ mice displayed a less aggressive cachectic phenotype, reduced tumor weight, and prolonged survival.ConclusionOur findings show for the first time a specific effect of activin-βC on muscle wasting and transcription factors involved in muscle protein degradation. The study indicates that activin-βC may be a novel therapy to abrogate cancer-associated weight loss and prolong survival.

Bone Pain and Muscle Weakness in Cancer Patients

“…[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. [90, 91]…”

Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 11th Cachexia Conference

“…They impressively showed that NF‐κB is activated in cachectic muscle in both paired box 7 progenitor cells and myofibers . Other studies buttress the view that increased forkhead box protein O (FoxO) signalling and the activation of the transcription factors NF‐κB, muscle RING finger 1 (MuRF1), and muscle atrophy F‐box (MAFbx) in skeletal muscle play major roles during cachexia onset and progression . MuRF1 and MAFbx are essentially involved in muscle atrophy development.…”

“…15,16 Other studies buttress the view that increased forkhead box protein O (FoxO) signalling and the activation of the transcription factors NF-κB, muscle RING finger 1 (MuRF1), and muscle atrophy F-box (MAFbx) in skeletal muscle play major roles during cachexia onset and progression. [17][18][19] MuRF1 and MAFbx are essentially involved in muscle atrophy development. Indeed, genes whose expression levels are commonly increased during multiple models of skeletal muscle atrophy, including cancer and sepsis, are MAFbx, MuRF1, and cathepsin, and there is evidence that each is a FoxO target gene.…”

Silver linings on the horizon: highlights from the 10th Cachexia Conference

“…He impressively showed that NF‐κB is activated in cachectic muscle in both PAX 7 progenitor cells and myofibers . Other studies buttress the view that increased forkhead box protein O (FoxO) signalling and the activation of the transcription factors NF‐κB, MuRF1 and muscle atrophy F‐box (MAFbx) in skeletal muscle play major roles during cachexia onset and progression . MuRF1 and MAFbx are essentially involved in muscle atrophy development.…”