Necdin is expressed in cachectic skeletal muscle to protect fibers from tumor-induced wasting

Sciorati, Clara; Touvier, Thierry; Buono, Roberta; Pessina, Patrizia; François, Stéphanie; Perrotta, Cristiana; Meneveri, Raffaella; Clementi, Emilio; Brunelli, Silvia

doi:10.1242/jcs.041665

Cited by 33 publications

(32 citation statements)

References 31 publications

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“…They differentiate into myotubes under low serum conditions; treatment with TGF-b commits them to differentiate into smooth muscle; treatment with BMP2 commits them to differentiate into osteocytes, as expected (49). Satellite cells were isolated as described (50). Polarized macrophages were propagated as described (51).…”

Section: Cell Culture and Mediamentioning

confidence: 97%

Transplanted Mesoangioblasts Require Macrophage IL-10 for Survival in a Mouse Model of Muscle Injury

Bosurgi

Corna

Vezzoli

et al. 2012

The Journal of Immunology

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The aim of this study was to verify whether macrophages influence the fate of transplanted mesoangioblasts—vessel-associated myogenic precursors—in a model of sterile toxin-induced skeletal muscle injury. We have observed that in the absence of macrophages, transplanted mesoangioblasts do not yield novel fibers. Macrophages retrieved from skeletal muscles at various times after injury display features that resemble those of immunoregulatory macrophages. Indeed, they secrete IL-10 and express CD206 and CD163 membrane receptors and high amounts of arginase I. We have reconstituted the muscle-associated macrophage population by injecting polarized macrophages before mesoangioblast injection: alternatively activated, immunoregulatory macrophages only support mesoangioblast survival and function. This action depends on the secretion of IL-10 in the tissue. Our results reveal an unanticipated role for tissue macrophages in mesoangioblast function. Consequently, the treatment of muscle disorders with mesoangioblasts should take into consideration coexisting inflammatory pathways, whose activation may prove crucial for its success.

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Section: Cell Culture and Mediamentioning

confidence: 97%

Transplanted Mesoangioblasts Require Macrophage IL-10 for Survival in a Mouse Model of Muscle Injury

Bosurgi

Corna

Vezzoli

et al. 2012

The Journal of Immunology

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“…Subsequently, the expression of myogenin and MRF4 (MRF members) is up-regulated in the cells beginning their terminal differentiation program, followed by a permanent exit from the cell cycle, the activation of muscle specific proteins, such as sarcomeric myosin, Defective skeletal muscle regeneration secondary to the potent inhibiting action of TNF-· has been shown to contribute to muscle wasting in a mouse model of cachexia (7,8). Indeed, we have demonstrated that necdin, a member of the MAGE family, plays an important role in skeletal muscle growth and repair in vivo, and is selectively expressed in the muscles of cachetic mice and that its expression is causally linked to a protective response of the tissue against tumor-induced wasting, the inhibition of myogenic differentiation and fiber regeneration (9). Despite such experimental evidence, studies on the role of muscle regeneration or defective regeneration in humans with cancer are still lacking.…”

Section: Introductionmentioning

confidence: 85%

“…This process is mainly linked to the activation of both IKKß/NF-κB-dependent and -independent pathways triggered by the increased signaling of TNF-· (13). TNF-· has been also shown to inhibit in vitro and in vivo myogenesis (7,9) as well as muscle regeneration by inhibiting cell fusion and by up-regulating caspase activity in myogenic stem cells (8). We have previously shown that the MAGE protein necdin is selectively expressed in the muscles of cachectic mice and have proven that its expression is causally linked to a protective response of the tissue against the tumor-induced wasting of myogenic differentiation and the inhibition of fiber regeneration (9).…”

Section: Discussionmentioning

confidence: 99%

“…TNF-· has been also shown to inhibit in vitro and in vivo myogenesis (7,9) as well as muscle regeneration by inhibiting cell fusion and by up-regulating caspase activity in myogenic stem cells (8). We have previously shown that the MAGE protein necdin is selectively expressed in the muscles of cachectic mice and have proven that its expression is causally linked to a protective response of the tissue against the tumor-induced wasting of myogenic differentiation and the inhibition of fiber regeneration (9). Necdin carries out this role mainly via interference with TNF-· signaling at various levels, including the regulation of the expression of TNFR1 and the regulation of the activity of caspases.…”

Section: Discussionmentioning

confidence: 99%

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Skeletal muscle of gastric cancer patients expresses genes involved in muscle regeneration

et al. 2010

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Abstract. Experimental studies have suggested that defective skeletal muscle regeneration could contribute to muscle wasting in cancer patients. However, data in humans are still lacking. In this study we aimed to assess the expression of the genes involved in muscle regeneration in gastric cancer patients. The RNA expression of the genes involved in muscle regeneration was assessed in the rectus abdominis muscle of patients with gastric cancer (n=30) and in age-matched control subjects (n=8). The Pax7 expression was significantly increased in the muscle of gastric cancer patients, either in the first stages of the disease or in stages IIIA and B. The increased expression was present both in stages IA and B and in stages II and III. The MyoD espression was also higher in the cancer patients than in the controls. However, the increased MyoD expression was present only in stages IA and B and not in the more advanced stages of the disease. The Myf5 expression, as well as that of the neonatal isoform of Myosin Heavy Chain (nMHC) did not differ significantly between the cancer patients and the controls. The necdin expression was negligible in healthy adult muscles and was significantly up-regulated in the muscle of gastric cancer patients. Its expression was highly increased in stages IA and B while it was similar to the control in stages II and III. The results of the present study show that in the skeletal muscle of gastric cancer patients, the expression of the genes involved in muscle regeneration is increased with respect to the controls. IntroductionCancer cachexia is a debilitating and life-threatening syndrome characterised by anorexia, body weight loss, loss of adipose tissue and skeletal muscle (1). Cachexia accounts for at least 20% of deaths in neoplastic patients. Cancer cachexia significantly impairs the quality of life as well as the response to anti-neoplastic therapies, thus increasing the morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of cancer cachexia and the principal cause of function impairment, fatigue and respiratory complications, mainly related to the hyperactivation of muscle proteolytic pathways. The loss of muscle protein, defined as muscle catabolism, occurs due to an imbalance between the rates of muscle protein synthesis and breakdown (1). In recent years, numerous studies have contributed to our understanding of the mechanisms underlying the increase of skeletal muscle protein breakdown in cancer cachexia and to the clarification of the relative contribution of different proteolytic pathways (2,3). Four major proteolytic systems exist in the skeletal muscle: The endosome-lysosome system that relies on the activity of acidic proteases, the caspases, the calpains, and the ubiquitinproteasome system (2,3). The bulk of muscle proteins (50-70%) exists in the actomyosin complexes and myofibrils, and in different catabolic conditions, contractile proteins in these complexes are degraded by the ubiquitin-proteasome system (4). However, the...

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“…10 Furthermore, we recently showed, in a mouse model and in human patients, that necdin counteracts muscle wasting specifically induced by cachexia, a pathology in which atrophy is associated with tumor load. 12,13 In this context, necdin exerts its protecting effect by interfering with tumor necrosis factor alpha (TNFa)-activated signaling at various levels and it is associated with a regenerative response of the muscle to wasting.…”

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confidence: 99%

Necdin enhances muscle reconstitution of dystrophic muscle by vessel-associated progenitors, by promoting cell survival and myogenic differentiation

et al. 2011

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Improving stem cell therapy is a major goal for the treatment of muscle diseases, where physiological muscle regeneration is progressively exhausted. Vessel-associated stem cells, such as mesoangioblasts (MABs), appear to be the most promising cell type for the cell therapy for muscular dystrophies and have been shown to significantly contribute to restoration of muscle structure and function in different muscular dystrophy models. Here, we report that melanoma antigen-encoding gene (MAGE) protein necdin enhances muscle differentiation and regeneration by MABs. When necdin is constitutively overexpressed, it accelerates their differentiation and fusion in vitro and it increases their efficacy in reconstituting regenerating myofibres in the a-sarcoglycan dystrophic mouse. Moreover, necdin enhances survival when MABs are exposed to cytotoxic stimuli that mimic the inflammatory dystrophic environment. Taken together, these data demonstrate that overexpression of necdin may be a crucial tool to boost therapeutic applications of MABs in dystrophic muscle.

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Necdin is expressed in cachectic skeletal muscle to protect fibers from tumor-induced wasting

Cited by 33 publications

References 31 publications

Transplanted Mesoangioblasts Require Macrophage IL-10 for Survival in a Mouse Model of Muscle Injury

Transplanted Mesoangioblasts Require Macrophage IL-10 for Survival in a Mouse Model of Muscle Injury

Skeletal muscle of gastric cancer patients expresses genes involved in muscle regeneration

Necdin enhances muscle reconstitution of dystrophic muscle by vessel-associated progenitors, by promoting cell survival and myogenic differentiation

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