Sonic Hedgehog Therapy in a Mouse Model of Age-Associated Impairment of Skeletal Muscle Regeneration

Piccioni, Andrea; Gaetani, Eleonora; Neri, Valentina; Gatto, Ilaria; Palladino, Mariangela; Silver, Marcy; Smith, Roy C.; Giarretta, Igor; Pola, Enrico; Hlatky, Lynn; Pola, Roberto

doi:10.1093/gerona/glt076

Cited by 38 publications

(35 citation statements)

References 37 publications

(63 reference statements)

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“…In embryos, somite determination is dependent on neural tube-derived Shh, 30 whereas secondary myogenesis in the limb is dependent on bone-derived Indian hedgehog. 31 Recently, Shh gene therapy was shown to be able to restore myogenesis in aged mice 32 ; nevertheless, in this setting, Shh was suggested to promote myogenesis indirectly via insulinlike growth factor-1 upregulation.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog-Dependent Regulation of Angiogenesis and Myogenesis Is Impaired in Aged Mice

Renault

Robbesyn

Chapouly

et al. 2013

ATVB

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Objective-The purpose of this study is to further document alteration of signal transduction pathways, more particularly of hedgehog (Hh) signaling, causing impaired ischemic muscle repair in old mice. Approach and Results-We used 12-week-old (young mice) and 20-to 24-month-old C57BL/6 mice (old mice) to investigate the activity of Hh signaling in the setting of hindlimb ischemia-induced angiogenesis and skeletal muscle repair. In this model, delayed ischemic muscle repair observed in old mice was associated with an impaired upregulation of Gli1. Sonic Hh expression was not different in old mice compared with young mice, whereas desert Hh (Dhh) expression was downregulated in the skeletal muscle of old mice both in healthy and ischemic conditions. The rescue of Dhh expression by gene therapy in old mice promoted ischemia-induced angiogenesis and increased nerve density; nevertheless, it failed to promote myogenesis or to increase Gli1 mRNA expression. After further investigation, we found that, in addition to Dhh, smoothened expression was significantly downregulated in old mice. We used smoothened haploinsufficient mice to demonstrate that smoothened knockdown by 50% is sufficient to impair activation of Hh signaling and ischemia-induced muscle repair. Conclusions-The present study demonstrates that Hh signaling is impaired in aged mice

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Section: Discussionmentioning

confidence: 99%

Hedgehog-Dependent Regulation of Angiogenesis and Myogenesis Is Impaired in Aged Mice

Renault

Robbesyn

Chapouly

et al. 2013

ATVB

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“…By contrast, SMO inhibition by cyclopamine treatment in injured animals results in muscle fibrosis and increased inflammation (Straface et al, 2009). Furthermore, although the regenerative ability of skeletal muscle declines in aging mice, intramuscular injection of a Shh-expressing vector was shown to successfully boost muscle repair to levels comparable with those found in much younger mice (Piccioni et al, 2013).…”

Section: Musclementioning

confidence: 99%

Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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The hedgehog (HH) pathway is well known for its mitogenic and morphogenic functions during development, and HH signaling continues in discrete populations of cells within many adult mammalian tissues. Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.

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“…Moreover, in the present study we also observed that up-regulation of Gli1 and Gli2 accompanied the Shh response to I/R injury. Among the Glis, Gli1 is the principal transcription factor in the Shh pathway, and many studies have shown that it is of great importance in skeletal muscle regeneration [20, 27, 28]. Furthermore, Gli2 activity has been confirmed to be sufficient and required for efficient MyoD treatment during skeletal myogenesis [29], which plays a major role in regulating muscle differentiation during embryogenesis and adult muscle regeneration [30].…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Sonic Hedgehog Against Ischemia/Reperfusion Injury in Mouse Skeletal Muscle via AKT/mTOR/p70S6K Signaling

Zeng¹,

Fu²,

Wang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Skeletal muscle ischemia/reperfusion (I/R) injury is a common and severe disease. Sonic hedgehog (Shh) plays a critical role in post-natal skeletal muscle regeneration. In the present study, the role of Shh in skeletal muscle I/R injury and the mechanisms involved were investigated. Methods: The expression of Shh, AKT/mTOR/p70S6K and apoptosis pathway components were evaluated following tourniquet-induced skeletal muscle I/R injury. Then, mice were subjected to systemic administration of cyclopamine or one-shot treatment of a plasmid encoding the human Shh gene (phShh) to examine the effects of Shh on I/R injury. Moreover, mice were subjected to systemic administration of NVP-BEZ235 to investigate the role of the AKT/mTOR/p70S6K pathway in Shh-triggered skeletal muscle protection. Results: We found that the levels of Shh, AKT/mTOR/p70S6K pathway components and Cleaved Caspase 3 and the Bax/Bcl2 ratio initially increased and then decreased at different time points post-I/R injury. Moreover, Shh protected skeletal muscle against I/R injury by alleviating muscle destruction, reducing interstitial fibrosis and inhibiting apoptosis, and these protective effects were abrogated when the AKT/mTOR/p70S6K pathway was inhibited. Conclusion: Collectively, these data suggest that Shh signaling exerts a protective role through the AKT/mTOR/p70S6K signaling pathway during skeletal muscle I/R injury. Thus, Shh signaling may be a therapeutic target for protecting skeletal muscle from I/R injury.

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Sonic Hedgehog Therapy in a Mouse Model of Age-Associated Impairment of Skeletal Muscle Regeneration

Cited by 38 publications

References 37 publications

Hedgehog-Dependent Regulation of Angiogenesis and Myogenesis Is Impaired in Aged Mice

Hedgehog-Dependent Regulation of Angiogenesis and Myogenesis Is Impaired in Aged Mice

Roles for Hedgehog signaling in adult organ homeostasis and repair

Protective Effects of Sonic Hedgehog Against Ischemia/Reperfusion Injury in Mouse Skeletal Muscle via AKT/mTOR/p70S6K Signaling

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