Phosphodiesterase (PDE) inhibitor torbafylline (HWA 448) attenuates burn-induced rat skeletal muscle proteolysis through the PDE4/cAMP/EPAC/PI3K/Akt pathway

Joshi, Rashika; Kadeer, Nijiati; Sheriff, Sulaiman; Friend, Lou Ann; James, J. Howard; Balasubramaniam, Ambikaipakan

doi:10.1016/j.mce.2014.06.012

Cited by 17 publications

(32 citation statements)

References 66 publications

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“…; Joshi et al. ). We thus examined the PDE4D expression in terms of PDE4D long isoforms (PDE4D‐L) (including PDE4D3 (76 kDa), PDE4D4 (91 kDa), and PDE4D5 (84 kDa)) and short isoforms (PDE4D‐S (including PDE4D1 (66 kDa) and PDE4D2 (58 kDa)) (Bolger et al.…”

Section: Resultsmentioning

confidence: 99%

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Role of phosphodiesterase 4 expression in the Epac1 signaling-dependent skeletal muscle hypertrophic action of clenbuterol

et al. 2016

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Clenbuterol (CB), a selective β 2‐adrenergic receptor (AR) agonist, induces muscle hypertrophy and counteracts muscle atrophy. However, it is paradoxically less effective in slow‐twitch muscle than in fast‐twitch muscle, though slow‐twitch muscle has a greater density of β‐AR. We recently demonstrated that Epac1 (exchange protein activated by cyclic AMP [cAMP]1) plays a pivotal role in β 2‐AR‐mediated masseter muscle hypertrophy through activation of the Akt and calmodulin kinase II (CaMKII)/histone deacetylase 4 (HDAC4) signaling pathways. Here, we investigated the role of Epac1 in the differential hypertrophic effect of CB using tibialis anterior muscle (TA; typical fast‐twitch muscle) and soleus muscle (SOL; typical slow‐twitch muscle) of wild‐type (WT) and Epac1‐null mice (Epac1KO). The TA mass to tibial length (TL) ratio was similar in WT and Epac1KO at baseline and was significantly increased after CB infusion in WT, but not in Epac1KO. The SOL mass to TL ratio was also similar in WT and Epac1KO at baseline, but CB‐induced hypertrophy was suppressed in both mice. In order to understand the mechanism involved, we measured the protein expression levels of β‐AR signaling‐related molecules, and found that phosphodiesterase 4 (PDE4) expression was 12‐fold greater in SOL than in TA. These results are consistent with the idea that increased PDE4‐mediated cAMP hydrolysis occurs in SOL compared to TA, resulting in a reduced cAMP concentration that is insufficient to activate Epac1 and its downstream Akt and CaMKII/HDAC4 hypertrophic signaling pathways in SOL of WT. This scenario can account for the differential effects of CB on fast‐ and slow‐twitch muscles.

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Section: Resultsmentioning

confidence: 99%

“…More importantly, PDE inhibition with torbafylline, a nonselective PDE inhibitor, attenuates burn‐induced skeletal muscle atrophy through the PDE4/cAMP/Epac/phosphoinositol 3‐kinase (PI3K)/Akt/mTOR pathway in vivo (Joshi et al. ).…”

Section: Discussionmentioning

confidence: 99%

Role of phosphodiesterase 4 expression in the Epac1 signaling-dependent skeletal muscle hypertrophic action of clenbuterol

et al. 2016

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“…The majority of the muscles wasting studies have demonstrated that autophagy system uses lysosomal enzymes (like cathepsin L) for the processing of damaged cellular components [12]. There are some studies which have reported enhanced cathepsin L activity without any change in the level of autophagy related markers under atrophic conditions [13][14][15]. These studies highlight the possibility of cathepsin L dependent and independent autophagy systems.…”

Section: Introductionmentioning

confidence: 95%

“…The activated Epac-Rap GTPase pathway increases the level of phosphorylated-Akt and stimulates the protein anabolic pathways by activating the PI3K/Akt axis. This axis shows its positive effects on protein synthesis and inhibitory effects on protein degradation by elevating the level of phospho-GSK3␤ and phosphomTOR and decreasing the level of phospho-FoxO1 [13,93,94]. In addition, torbafylline treatment down-regulates mRNA expression of E3 ligases, cathepsin L, and calpain and regulates the proteolytic pathways in burn-induced injury.…”

Section: Torbafylline (Hwa 448)mentioning

confidence: 99%

“…In addition, torbafylline treatment down-regulates mRNA expression of E3 ligases, cathepsin L, and calpain and regulates the proteolytic pathways in burn-induced injury. Besides this, torbafylline regulates muscle proteolysis by down-regulating the level of proinflammatory cytokines (IL-6 and TNF␣) probably by stimulating both (Epac and PKA) cAMP dependent receptor proteins [13,95,96]. In addition to injury induced atrophy, torbafylline attenuates inflammatory cytokine levels in a large number of muscle wasting models such as diabetes, cancer and sepsis [92,97,98].…”

Section: Torbafylline (Hwa 448)mentioning

confidence: 99%

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Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action

Dutt

Gupta

Dabur

et al. 2015

Pharmacological Research

143

110

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Effects of cyclic nucleotide phosphodiesterases (PDEs) on mitochondrial skeletal muscle functions

Tetsi

Charles

Paradis

et al. 2016

Cell. Mol. Life Sci.

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Mitochondria play a critical role in skeletal muscle metabolism and function, notably at the level of tissue respiration, which conduct muscle strength as well as muscle survival. Pathological conditions induce mitochondria dysfunctions notably characterized by free oxygen radical production disturbing intracellular signaling. In that way, the second messengers, cyclic AMP and cyclic GMP, control intracellular signaling at the physiological and transcription levels by governing phosphorylation cascades. Both nucleotides are specifically and selectively hydrolyzed in their respective 5'-nucleotide by cyclic nucleotide phosphodiesterases (PDEs), which constitute a multi-genic family differently tissue distributed and subcellularly compartmentalized. These PDEs are presently recognized as therapeutic targets for cardiovascular, pulmonary, and neurologic diseases. However, very few data concerning cyclic nucleotides and PDEs in skeletal muscle, specifically in mitochondria, are reported in the literature. The knowledge of PDE implication in mitochondrial signaling would be helpful for resolving critical mitochondrial dysfunctions in skeletal muscle.

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Phosphodiesterase (PDE) inhibitor torbafylline (HWA 448) attenuates burn-induced rat skeletal muscle proteolysis through the PDE4/cAMP/EPAC/PI3K/Akt pathway

Cited by 17 publications

References 66 publications

Role of phosphodiesterase 4 expression in the Epac1 signaling-dependent skeletal muscle hypertrophic action of clenbuterol

Role of phosphodiesterase 4 expression in the Epac1 signaling-dependent skeletal muscle hypertrophic action of clenbuterol

Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action

Effects of cyclic nucleotide phosphodiesterases (PDEs) on mitochondrial skeletal muscle functions

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