Modulation of Caspase Activity Regulates Skeletal Muscle Regeneration and Function in Response to Vasopressin and Tumor Necrosis Factor

Moresi, Viviana; García-Alvarez, Gisela; Pristerà, Alessandro; Rizzuto, Emanuele; Albertini, Maria Cristina; Rocchi, Marco; Marazzi, Giovanna; Sassoon, David; Adamo, Sergio; Coletti, Dario

doi:10.1371/journal.pone.0005570

Cited by 42 publications

(36 citation statements)

References 70 publications

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“…during physical exercise (40), and AVP injection improves in vivo muscle regeneration (41). Based on these observations, AVP is likely to play a physiological role in skeletal muscle development and homeostasis.…”

Section: Discussionmentioning

confidence: 97%

Phospholipase D Regulates Myogenic Differentiation through the Activation of Both mTORC1 and mTORC2 Complexes

Jaafar

Zeiller

Pirola

et al. 2011

Journal of Biological Chemistry

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How phospholipase D (PLD) is involved in myogenesis remains unclear. At the onset of myogenic differentiation of L6 cells induced by the PLD agonist vasopressin in the absence of serum, mTORC1 complex was rapidly activated, as reflected by phosphorylation of S6 kinase1 (S6K1). Both the long (p85) and short (p70) S6K1 isoforms were phosphorylated in a PLD1-dependent way. Short rapamycin treatment specifically inhibiting mTORC1 suppressed p70 but not p85 phosphorylation, suggesting that p85 might be directly activated by phosphatidic acid. Vasopressin stimulation also induced phosphorylation of Akt on Ser-473 through PLD1-dependent activation of mTORC2 complex. In this model of myogenesis, mTORC2 had a positive role mostly unrelated to Akt activation, whereas mTORC1 had a negative role, associated with S6K1-induced Rictor phosphorylation. The PLD requirement for differentiation can thus be attributed to its ability to trigger via mTORC2 activation the phosphorylation of an effector that could be PKC␣. Moreover, PLD is involved in a counter-regulation loop expected to limit the response. This study thus brings new insights in the intricate way PLD and mTOR cooperate to control myogenesis.The mammalian target of rapamycin (mTOR) 2 is a serine/ threonine protein kinase that integrates signals provided by growth factors, nutrient availability, energy levels, or redox status to adapt protein synthesis and major cell functions such as growth, proliferation, and survival to the physiological conditions (1). It exists in two complexes, mTORC1 and mTORC2, that are differentially regulated, have distinct effector substrates, and are differentially sensitive to rapamycin, a bacterial macrolide endowed with anti-proliferative and immunosuppressant activities. Whereas activity of mTORC1 complex is highly sensitive to acute treatment by nanomolar concentrations of rapamycin, only prolonged rapamycin treatment is able to induce mTORC2 disruption and inactivation (2-4).A recently identified regulatory signal impacting on mTOR activity is the production of phosphatidic acid (PA) by phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine (5, 6). PLD, which can be activated by a variety of hormones, growth factors, and cytokines, is present in most tissues under two isoforms, PLD1 and PLD2, endowed with different properties, regulations, and functions (7). Phosphatidic acid has been shown to specifically bind to mTOR protein on the FRB domain, a regulatory site also responsible for the binding of rapamycin in complex with protein FKBP12. The protein/ phospholipid interaction causes the activation of mTOR kinase, and rapamycin has been proposed to exert its inhibitory effects on mTOR by competing with PA and blocking PA-mediated activation (8 -10).Signaling by mTOR has become a topic of particular interest in the field of skeletal muscle biology due to the critical involvement of this kinase in muscle remodeling. Thus, muscle hypertrophy induced by exercise has been shown to involve mTOR signaling (11-13). Rapamycin inhibits...

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Section: Discussionmentioning

confidence: 97%

Phospholipase D Regulates Myogenic Differentiation through the Activation of Both mTORC1 and mTORC2 Complexes

Jaafar

Zeiller

Pirola

et al. 2011

Journal of Biological Chemistry

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“…Therefore, it would not be surprising if the deficits in muscle fiber regeneration and recovery seen in Hsp70 −/− mice in this study are also related to impairments in protein quality control due to the absence of intracellular Hsp70. It is well documented that upregulation of intracellular Hsp70 in skeletal muscle protects against muscle damage, enhances regenerating fiber size, promotes functional sparing and preserves myofiber size during atrophy conditions [8], [16], [17], [18], [59]. Perhaps the most striking finding related to Hsp70 overexpression was the recent study published by Gehrig et al, who demonstrated that Hsp70 transgenic overexpression in skeletal muscle and/or pharmacological induction of Hsp70 could improve muscle quality and function in a mouse model of muscular dystrophy.…”

Section: Discussionmentioning

confidence: 99%

Loss of the Inducible Hsp70 Delays the Inflammatory Response to Skeletal Muscle Injury and Severely Impairs Muscle Regeneration

et al. 2013

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Skeletal muscle regeneration following injury is a highly coordinated process that involves transient muscle inflammation, removal of necrotic cellular debris and subsequent replacement of damaged myofibers through secondary myogenesis. However, the molecular mechanisms which coordinate these events are only beginning to be defined. In the current study we demonstrate that Heat shock protein 70 (Hsp70) is increased following muscle injury, and is necessary for the normal sequence of events following severe injury induced by cardiotoxin, and physiological injury induced by modified muscle use. Indeed, Hsp70 ablated mice showed a significantly delayed inflammatory response to muscle injury induced by cardiotoxin, with nearly undetected levels of both neutrophil and macrophage markers 24 hours post-injury. At later time points, Hsp70 ablated mice showed sustained muscle inflammation and necrosis, calcium deposition and impaired fiber regeneration that persisted several weeks post-injury. Through rescue experiments reintroducing Hsp70 intracellular expression plasmids into muscles of Hsp70 ablated mice either prior to injury or post-injury, we confirm that Hsp70 optimally promotes muscle regeneration when expressed during both the inflammatory phase that predominates in the first four days following severe injury and the regenerative phase that predominates thereafter. Additional rescue experiments reintroducing Hsp70 protein into the extracellular microenvironment of injured muscles at the onset of injury provides further evidence that Hsp70 released from damaged muscle may drive the early inflammatory response to injury. Importantly, following induction of physiological injury through muscle reloading following a period of muscle disuse, reduced inflammation in 3-day reloaded muscles of Hsp70 ablated mice was associated with preservation of myofibers, and increased muscle force production at later time points compared to WT. Collectively our findings indicate that depending on the nature and severity of muscle injury, therapeutics which differentially target both intracellular and extracellular localized Hsp70 may optimally preserve muscle tissue and promote muscle functional recovery.

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“…Skeletal muscle wasting contributes substantially to morbidity in septic shock and is contributed to by inhibition of muscle regeneration by TNF. Vasopressin counteracted the effects of TNF in myocyte cell cultures [62] .…”

Section: The Effects Of Vasopressin On Other Organ Dysfunctionmentioning

confidence: 95%

Vasopressin and Its Immune Effects in Septic Shock

Russell

Walley²

2010

J Innate Immun

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clinical studies of vasopressin infusion in septic shock have shown that vasopressin infusion increases blood pressure, decreases requirements for norepinephrine and improves renal function. However, vasopressin could decrease coronary, cerebral and mesenteric perfusion. A multicenter trial of vasopressin versus norepinephrine in septic shock found no overall difference in mortality. Vasopressin may decrease mortality in patients with less severe septic shock. Vasopressin plus corticosteroid treatment may decrease mortality compared to corticosteroids plus norepinephrine. Potential mechanisms are that vasopressin plus corticosteroids beneficially alter immunity in septic shock.

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Modulation of Caspase Activity Regulates Skeletal Muscle Regeneration and Function in Response to Vasopressin and Tumor Necrosis Factor

Cited by 42 publications

References 70 publications

Phospholipase D Regulates Myogenic Differentiation through the Activation of Both mTORC1 and mTORC2 Complexes

Phospholipase D Regulates Myogenic Differentiation through the Activation of Both mTORC1 and mTORC2 Complexes

Loss of the Inducible Hsp70 Delays the Inflammatory Response to Skeletal Muscle Injury and Severely Impairs Muscle Regeneration

Vasopressin and Its Immune Effects in Septic Shock

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