NF-κB Negatively Impacts the Myogenic Potential of Muscle-derived Stem Cells

Lü, Aiping; Proto, Jonathan D.; Guo, Lulin; Tang, Ying; Lavasani, Mitra; Tilstra, Jeremy S.; Niedernhofer, Laura J.; Wang, Bing; Guttridge, Denis C.; Robbins, Paul D.; Huard, Johnny

doi:10.1038/mt.2011.261

Cited by 55 publications

(52 citation statements)

References 36 publications

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“…Several lines of evidence suggest that upregulated NFκB signaling could negatively affect muscle regeneration in these inflammatory pathologies. Decreasing activated p65 using a haploinsufficient mouse model increases myoblast proliferation and myogenic index [35]. In the present study, inhibition of NFκB signaling using celastrol reduced the myogenic defect and increased myotubes diameters in dysferlin-deficiency.…”

Section: Discussionmentioning

confidence: 48%

Myogenesis in dysferlin-deficient myoblasts is inhibited by an intrinsic inflammatory response

Cohen¹,

Cohen²,

Partridge³

2012

Neuromuscular Disorders

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Limb-girdle muscular dystrophy type 2B results from mutations in dysferlin, a membraneassociated protein involved in cellular membrane repair. Primary myoblast cultures derived from dysferlinopathy patients show reduced myogenic potential, suggesting that dysferlin may regulate myotube fusion and be required for muscle regeneration. These observations contrast with the findings that muscle develops normally in pre-symptomatic dysferlinopathy patients. To better understand the role of dysferlin in myogenesis, we investigated this process in vitro using cells derived from two mouse models of dysferlinopathy: SJL/J and A/J mice. We observed that myotubes derived from dysferlin-deficient muscle were of significantly smaller diameters, contained fewer myonuclei, and displayed reduced myogenic gene expression compared to dysferlin-sufficient cells. Together, these findings suggest that the absence of dysferlin from myoblasts is detrimental to myogenesis. Pro-inflammatory NFκB signaling was upregulated in dysferlin-deficient myotubes; the anti-inflammatory agent celastrol reduced the NFκB activation and improved myogenesis in dysferlin-deficient cultures. The results suggest that decreased myotube fusion in dysferlin deficiency is attributable to intrinsic inflammatory activation and can be improved using anti-inflammatory mediators.

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Section: Discussionmentioning

confidence: 48%

Myogenesis in dysferlin-deficient myoblasts is inhibited by an intrinsic inflammatory response

Cohen¹,

Cohen²,

Partridge³

2012

Neuromuscular Disorders

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“…1) and induce muscle atrophy (reviewed in Refs. 13,17) in part via MuRF1(3), while NF-B inhibition can enhance myogenesis and improve muscle regeneration in vivo (18). Here we show the phosphorylation (activation) state of the NF-B p65 subunit was elevated fivefold in the perioperative muscle of MuIS (ϩ) patients with a coordinate and nearly twofold elevation of TWEAK-R protein.…”

Section: Discussionmentioning

confidence: 73%

Muscle inflammation susceptibility: a prognostic index of recovery potential after hip arthroplasty?

Bamman

Ferrando

Evans

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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While elective total hip arthroplasty (THA) for end-stage osteoarthritis (OA) improves pain, mobility function, and quality of life in most cases, a large proportion of patients suffer persistent muscle atrophy, pain, and mobility impairment. Extensive skeletal muscle damage is unavoidable in these surgical procedures, and it stands to reason that poor recovery and long-term mobility impairment among some individuals after THA is linked to failed muscle regeneration and regrowth following surgery and that local muscle inflammation susceptibility (MuIS) is a major contributing factor. Here we present results of two integrated studies. In study 1, we compared muscle inflammation and protein metabolism signaling in elective THA ( n = 15) vs. hip fracture/trauma (HFX; n = 11) vs. nonsurgical controls (CON; n = 19). In study 2, we compared two subgroups of THA patients dichotomized into MuIS(+) ( n = 7) or MuIS(−) ( n = 7) based on muscle expression of TNF-like weak inducer of apoptosis (TWEAK) receptor (Fn14). As expected, HFX demonstrated overt systemic and local muscle inflammation and hypermetabolism. By contrast, no systemic inflammation was detected in elective THA patients; however, local muscle inflammation in the perioperative limb was profound in MuIS(+) and was accompanied by suppressed muscle protein synthesis compared with MuIS(−). Muscle from the contralateral limb of MuIS(+) was unaffected, providing evidence of a true inflammation susceptibility localized to the muscle surrounding the hip with end-stage OA. We suggest MuIS status assessed at the time of surgery may be a useful prognostic index for muscle recovery potential and could therefore provide the basis for a personalized approach to postsurgery rehabilitation.

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“…In culture, activation of the same classical pathway in myoblasts has been shown by multiple groups, including our own, to negatively regulate differentiation. In fact, in conditions such as muscular dystrophy, the constitutive activation of NF-κB in muscle was shown to function as a major inhibitor of muscle regeneration, which is one of the hallmark features of degenerative muscles in this pathology [120, 121]. In cancer cachexia, we showed that NF-κB activity was absent in quiescent satellite cells, but highly induced within Pax7+ cells in tumor-bearing mice [104].…”

Section: Introductionmentioning

confidence: 99%

Impaired regeneration: A role for the muscle microenvironment in cancer cachexia

Talbert

Guttridge

2016

Seminars in Cell & Developmental Biology

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While changes in muscle protein synthesis and degradation have long been known to contribute to muscle wasting, a body of literature has arisen which suggests that regulation of the satellite cell and its ensuing regenerative program are impaired in atrophied muscle. Lessons learned from cancer cachexia suggest that this regulation is simply not a consequence, but a contributing factor to the wasting process. In addition to satellite cells, evidence from mouse models of cancer cachexia also suggests that non-satellite progenitor cells from the muscle microenvironment are also involved. This chapter in the series reviews the evidence of dysfunctional muscle repair in multiple wasting conditions. Potential mechanisms for this dysfunctional regeneration are discussed, particularly in the context of cancer cachexia.

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NF-κB Negatively Impacts the Myogenic Potential of Muscle-derived Stem Cells

Cited by 55 publications

References 36 publications

Myogenesis in dysferlin-deficient myoblasts is inhibited by an intrinsic inflammatory response

Myogenesis in dysferlin-deficient myoblasts is inhibited by an intrinsic inflammatory response

Muscle inflammation susceptibility: a prognostic index of recovery potential after hip arthroplasty?

Impaired regeneration: A role for the muscle microenvironment in cancer cachexia

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