Attenuation of p38α MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells

Papaconstantinou, John; Wang, Chen Z.; Zhang, Min; Yang, San; DeFord, James H.; Bulavin, Dmitry V.; Ansari, Naseem H.

doi:10.18632/aging.100802

Cited by 24 publications

(28 citation statements)

References 62 publications

(101 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with the notion that p38α is a significant regulator of cell senescence, aged DN-p38α AF/+ mice are resistant to age-dependent decline in the proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates (Papaconstantinou et al, 2009, 2015; Wong et al, 2009). This has led to the hypothesis that in the periphery, p38 modulates the regenerative capacity of tissues that rely upon a progenitor population (e.g., muscle, liver, and pancreas).…”

Section: 0 Introductionsupporting

confidence: 67%

Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning

Cortez

Bulavin

et al. 2017

Behavioural Brain Research

Self Cite

View full text Add to dashboard Cite

A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age-related senescence of self-renewal occurs simultaneously with chronic up-regulation of the p38MAPKalpha (p38α) signaling pathway, we used the dominant negative mouse model for attenuated p38α activity (DN-p38αAF/+ ) in which Thr180 and Tyr182 are mutated (T→A/Y→F) to prevent phosphorylation activation (DN-p38αAF/+) and kinase activity. As a result, aged DN-p38αAF/+ mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates. Aging is the major risk factor for non-inherited forms of Alzheimer’s disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual’s relative risk. In the present study, we evaluated aged DN-p38αAF/+ and wildtype littermates in a series of behavioral paradigms to test if p38α mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38αAF/+ and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38αAF/+ exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN-p38αAF/+, we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38αAF/+ mice compared to wildtype littermates. Our findings support the notion that p38α inhibition has therapeutic utility in aging diseases that affect cognition, such as AD.

show abstract

Section: 0 Introductionsupporting

confidence: 67%

Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning

Cortez

Bulavin

et al. 2017

Behavioural Brain Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Paradoxically, in addition to its known role in satellite cell activation 76 , p38 α/β-MAPK signalling can also activate p16 Ink4a to promote cellular senescence 99 . A genetic link between p38α/β-MAPK and p16 Ink4a was recently demonstrated in skeletal muscle, when it was found that p16 Ink4a protein levels were reduced in the gastrocnemius muscle of animals expressing a dominant-negative p38α allele, although future studies will need to verify this connection in satellite cells 100 . Cumulatively, these data suggest that an age-regulated intrinsic p38 signalling-axis exists in the satellite cell pool.…”

Section: Satellite Cell Fate In Aging Musclementioning

confidence: 94%

Molecular circuitry of stem cell fate in skeletal muscle regeneration, ageing and disease

Almada

Wagers

2016

Nat Rev Mol Cell Biol

215

222

View full text Add to dashboard Cite

Satellite cells are adult myogenic stem cells that function to repair damaged muscle. The enduring capacity for muscle regeneration requires efficient satellite cell expansion after injury, differentiation to produce myoblasts that can reconstitute damaged fibers, and self-renewal to replenish the muscle stem cell pool for subsequent rounds of injury and repair. Emerging studies indicate that misregulations of satellite cell fate and function contribute to age-associated muscle dysfunction and influence the severity of muscle diseases, including Duchenne Muscular Dystrophy (DMD). It has also become apparent that satellite cell fate during muscle regeneration, aging, and in the context of DMD is governed by an intricate network of intrinsic and extrinsic regulators. Targeted manipulation of this network may offer unique opportunities for muscle regenerative medicine.

show abstract

“…Demonstration that the decreased expresion of p38α/β and its targeted activation of aging phenotype markers addresses this question in that; a) inhibition of p38α/β decreases the expression of markers of aging; b) the attenuation of p38α/β in a haploinsuficient p38α +/− mouse delays the aging of pancreatic β-cells and skeletal muscle progenitor cells [134,136]. The p38MAPK inhibitors provide an experimental linkage of the molecular mechanisms activated by inflammtion-oxidative stress to the molecular mechanisms of initiation of PTB and pPROM.…”

Section: Significancementioning

confidence: 99%

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

Menon

Papaconstantinou

2016

Expert Opinion on Therapeutic Targets

Self Cite

View full text Add to dashboard Cite

Introduction Spontaneous preterm birth (PTB) and preterm premature rupture of the membranes (pPROM) remain as a major clinical and therapeutic problem for intervention and management. Current strategies, based on our knowledge of pathways of preterm labor, have only been effective, in part, due to major gaps in our existing knowledge of risks and risk specific pathways. Areas covered Recent literature has identified physiologic aging of fetal tissues as a potential mechanistic feature of normal parturition. This process is affected by telomere dependent and p38 mitogen activated protein kinase (MAPK) induced senescence activation. Pregnancy associated risk factors can cause pathologic activation of this pathway that can cause oxidative stress induced p38 MAPK activation leading to senescence and premature aging of fetal tissues. Premature aging is associated with sterile inflammation capable of triggering preterm labor or preterm premature rupture of membranes. Preterm activation of p38MAPK can be considered as a key contributor to adverse pregnancies. Expert Opinion This review considers p38MAPK activation as a potential target for therapeutic interventions to prevent adverse pregnancy outcomes mediated by stress factors. In this review, we propose multiple strategies to prevent p38MAPK activation and its functional effects.

show abstract

Attenuation of p38α MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells

Cited by 24 publications

References 62 publications

Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning

Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning

Molecular circuitry of stem cell fate in skeletal muscle regeneration, ageing and disease

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

Contact Info

Product

Resources

About