Age dependent increase in the levels of osteopontin inhibits skeletal muscle regeneration

Paliwal, Preeti; Pishesha, Novalia; Wijaya, Denny; Conboy, Irina M.

doi:10.18632/aging.100477

Cited by 70 publications

(79 citation statements)

References 35 publications

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“…2012). To provide an insight into the role of OPN‐a expression on skeletal muscle transcriptomics, we performed transcriptional profiling on muscle tissue sections following intramuscular OPN‐a overexpression in 3‐month‐old BLA/J mice.…”

Section: Resultsmentioning

confidence: 99%

“…2009) and promote regeneration following acute injury in aged mice (Paliwal et al . 2012). Targeting OPN‐a, but not OPN‐c, signalling in human skeletal muscle might be a useful therapeutic strategy, because OPN does exert some positive effects on skeletal muscle regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…2008; Paliwal et al . 2012). However, functional differences between spliced isoforms in the regenerating muscle microenvironment have not been characterized.…”

Section: Introductionmentioning

confidence: 99%

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OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages

Many

Yokosaki

Uaesoontrachoon

et al. 2016

Experimental Physiology

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New Findings What is the central question of this study? What is the functional relevance of OPN isoform expression in muscle pathology? What is the main finding and its importance? The full‐length human OPN‐a isoform is the most pro‐inflammatory isoform in the muscle microenvironment, acting on macrophages and myoblasts in an RGD‐integrin‐dependent manner. OPN‐a upregulates expression of tenascin‐C (TNC), a known Toll‐like receptor 4 (TLR4) agonist. Blocking TLR4 signalling inhibits the pro‐inflammatory effects of OPN‐a, suggesting that a potential mechanism of OPN action is by promoting TNC–TLR4 signalling. Although osteopontin (OPN) is an important mediator of muscle remodelling in health and disease, functional differences in human spliced OPN variants in the muscle microenvironment have not been characterized. We thus sought to define the pro‐inflammatory activities of human OPN isoforms (OPN‐a, OPN‐b and OPN‐c) on cells present in regenerating muscle. OPN transcripts were quantified in normal and dystrophic human and dog muscle. Human macrophages and myoblasts were stimulated with recombinant human OPN protein isoforms, and cytokine mRNA and protein induction was assayed. OPN isoforms were greatly increased in dystrophic human (OPN‐a > OPN‐b > OPN‐c) and dog muscle (OPN‐a = OPN‐c). In healthy human muscle, mechanical loading also upregulated OPN‐a expression (eightfold; P < 0.01), but did not significantly upregulate OPN‐c expression (twofold; P > 0.05). In vitro, OPN‐a displayed the most pronounced pro‐inflammatory activity among isoforms, acting on both macrophages and myoblasts. In vitro and in vivo data revealed that OPN‐a upregulated tenascin‐C (TNC), a known Toll‐like receptor 4 (TLR4) agonist. Inhibition of TLR4 signalling attenuated OPN‐mediated macrophage cytokine production. In summary, OPN‐a is the most abundant and functionally active human spliced isoform in the skeletal muscle microenvironment. Here, OPN‐a promotes pro‐inflammatory signalling in both macrophages and myoblasts, possibly through induction of TNC–TLR4 signalling. Together, our findings suggest that specific targeting of OPN‐a and/or TNC signalling in the damaged muscle microenvironment may be of therapeutic relevance.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages

Many

Yokosaki

Uaesoontrachoon

et al. 2016

Experimental Physiology

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“…Paliwal and coworkers [172] reported that age-dependent increases in the levels of osteopontin (OPN) inhibit skeletal muscle regeneration. The transient upregulation of OPN after muscle injury has been demonstrated to play a positive role in overall regeneration [173]; however, in cultured myoblasts, OPN has been shown to inhibit cell migration and differentiation [174] as well as muscle regeneration in mdx mice [175].…”

Section: Muscle Regeneration Is Affected In Aging and Muscle Diseasesmentioning

confidence: 99%

The Basis of Muscle Regeneration

Musarò

2014

Advances in Biology

117

138

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Muscle regeneration recapitulates many aspects of embryonic myogenesis and is an important homeostatic process of the adult skeletal muscle, which, after development, retains the capacity to regenerate in response to appropriate stimuli, activating the muscle compartment of stem cells, namely, satellite cells, as well as other precursor cells. Moreover, significant evidence suggests that while stem cells represent an important determinant for tissue regeneration, a "qualified" environment is necessary to guarantee and achieve functional results. It is therefore plausible that the loss of control over these cell fate decisions could lead to a pathological transdifferentiation, leading to pathologic defects in the regenerative process. This review provides an overview about the general aspects of muscle development and discusses the cellular and molecular aspects that characterize the five interrelated and time-dependent phases of muscle regeneration, namely, degeneration, inflammation, regeneration, remodeling, and maturation/functional repair.

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“…Neutrophile Macrophage Lymphocyte T en présence de macrophages de sujets jeunes [41]. Les perturbations dans le recrutement et l'activité des leucocytes peuvent donc nuire à la régénération des muscles vieillissants [42].…”

Section: Mastocyteunclassified