Phosphodiesterase 4 inhibition restrains muscle proteolysis in diabetic rats by activating PKA and EPAC/Akt effectors and inhibiting FoxO factors

Arcaro, Carlos Alberto; Assis, Renata Pires; Oliveira, Juliana Oriel; Zanon, Neusa Maria; Paula-Gomes, Sílvia; Navegantes, Luiz Carlos Carvalho; Kettelhut, Ísis C.; Brunetti, Iguatemy Lourenço; Baviera, Amanda Martins

doi:10.1016/j.lfs.2021.119563

Cited by 8 publications

(5 citation statements)

References 38 publications

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“…Our results showed that treatment with roflumilast antagonized rotenone-induced neurotoxicity through downregulating GSK-3β, NF-κB, FoxO1 and caspase-3. These findings are in harmony with previous studies emphasizing the same fruitful impact of PDE4 inhibition in suppressing those injurious parameters in other degenerative models (Wang et al 2020b ; Arcaro et al 2021 ; Hasan et al 2022 ). Our study revealed that roflumilast exerted neuroprotective effects in rotenone-induced neurotoxicity in rats.…”

Section: Discussionsupporting

confidence: 92%

PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson’s disease in rats

et al. 2023

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Parkinson’s disease (PD) is the second most common progressive age-related neurodegenerative disorder. Paramount evidence shed light on the role of PI3K/AKT signaling activation in the treatment of neurodegenerative disorders. PI3K/AKT signaling can be activated via cAMP-dependent pathways achieved by phosphodiesterase 4 (PDE4) inhibition. Roflumilast is a well-known PDE4 inhibitor that is currently used in the treatment of chronic obstructive pulmonary disease. Furthermore, roflumilast has been proposed as a favorable candidate for the treatment of neurological disorders. The current study aimed to unravel the neuroprotective role of roflumilast in the rotenone model of PD in rats. Ninety male rats were allocated into six groups as follows: control, rotenone (1.5 mg/kg/48 h, s.c.), L-dopa (22.5 mg/kg, p.o), and roflumilast (0.2, 0.4 or 0.8 mg/kg, p.o). All treatments were administrated for 21 days 1 h after rotenone injection. Rats treated with roflumilast showed an improvement in motor activity and coordination as well as preservation of dopaminergic neurons in the striatum. Moreover, roflumilast increased cAMP level and activated the PI3K/AKT axis via stimulation of CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling cascades. Roflumilast also caused an upsurge in mTOR and Nrf2, halted GSK-3β and NF-ĸB, and suppressed FoxO1 and caspase-3. Our study revealed that roflumilast exerted neuroprotective effects in rotenone-induced neurotoxicity in rats. These neuroprotective effects were mediated via the crosstalk between CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling pathways which activates PI3K/AKT trajectory. Therefore, PDE4 inhibition is likely to offer a reliable persuasive avenue in curing PD via PI3K/AKT signaling activation. Graphical Abstract

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Section: Discussionsupporting

confidence: 92%

PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson’s disease in rats

et al. 2023

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“…For instance, we found proteins positively correlated with CpGs located in genes related to fatty acid metabolism, such as COMMD9 (involved in LDL regulation), 100 ARHGAP42 (associated with hypertension), 101 APOBEC1 (linked to weight loss and muscle development), 102 PTPRT, PTPRN2 (implicated in obesity), 103–106 and DACT1, DIO2, RPTOR, and PLEKHM3 (involved in muscle myogenesis and hypertrophy) 107–111 . Conversely, these proteins were negatively correlated with CpG sites located in genes such as KCNMA1, NOTCH1, CAMKK2 (related to skeletal muscle regeneration, proliferation, and differentiation), 112–117 DHRS3, DGKG, LPIN1, WNT5A (associated with obesity, metabolic syndrome, and lipid regulation), 118–120 LRRC2 (a mediator of mitochondrial and cardiac function), 121 and PDE4A (linked to diabetes) 122,123 . These associations provide valuable insights into the intricate relationships between specific genes, proteins, and exercise response.…”

Section: Discussionmentioning

confidence: 90%

“…[107][108][109][110][111] Conversely, these proteins were negatively correlated with CpG sites located in genes such as KCNMA1, NOTCH1, CAMKK2 (related to skeletal muscle regeneration, proliferation, and differentiation), [112][113][114][115][116][117] DHRS3, DGKG, LPIN1, WNT5A (associated with obesity, metabolic syndrome, and lipid regulation), [118][119][120] LRRC2 (a mediator of mitochondrial and cardiac function), 121 and PDE4A (linked to diabetes). 122,123 These associations provide valuable insights into the intricate relationships between specific genes, proteins, and exercise response. Based on the outcomes of this integration analysis, we strongly recommend prioritizing future investigations into the relationship between these genes/proteins.…”

Section: Discussionmentioning

confidence: 99%

Methylome and proteome integration in human skeletal muscle uncover group and individual responses to high‐intensity interval training

Jacques,

Landen,

Romero

et al. 2023

The FASEB Journal

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Exercise is a major beneficial contributor to muscle metabolism, and health benefits acquired by exercise are a result of molecular shifts occurring across multiple molecular layers (i.e., epigenome, transcriptome, and proteome). Identifying robust, across‐molecular level targets associated with exercise response, at both group and individual levels, is paramount to develop health guidelines and targeted health interventions. Sixteen, apparently healthy, moderately trained (VO2 max = 51.0 ± 10.6 mL min−1 kg−1) males (age range = 18–45 years) from the Gene SMART (Skeletal Muscle Adaptive Responses to Training) study completed a longitudinal study composed of 12‐week high‐intensity interval training (HIIT) intervention. Vastus lateralis muscle biopsies were collected at baseline and after 4, 8, and 12 weeks of HIIT. DNA methylation (~850 CpG sites) and proteomic (~3000 proteins) analyses were conducted at all time points. Mixed models were applied to estimate group and individual changes, and methylome and proteome integration was conducted using a holistic multilevel approach with the mixOmics package. A total of 461 proteins significantly changed over time (at 4, 8, and 12 weeks), whilst methylome overall shifted with training only one differentially methylated position (DMP) was significant (adj.p‐value < .05). K‐means analysis revealed cumulative protein changes by clusters of proteins that presented similar changes over time. Individual responses to training were observed in 101 proteins. Seven proteins had large effect‐sizes >0.5, among them are two novel exercise‐related proteins, LYRM7 and EPN1. Integration analysis showed bidirectional relationships between the methylome and proteome. We showed a significant influence of HIIT on the epigenome and more so on the proteome in human muscle, and uncovered groups of proteins clustering according to similar patterns across the exercise intervention. Individual responses to exercise were observed in the proteome with novel mitochondrial and metabolic proteins consistently changed across individuals. Future work is required to elucidate the role of these proteins in response to exercise.

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“…The integration analysis highlighted proteins both positively and negatively associated with specific CpGs, worthy following up in future replication/mechanistic studies. Interestingly of the 261 proteins highlighted in the results, we found proteins positively correlated with CpGs located in genes involved in fatty acid metabolism such as COMMD9 , (involved in LDL regulation) [88]; hypertension ( ARHGAP42) [89]; weight loss and muscle development ( APOBEC1 ) [90]; obesity ( PTPRT and PTPRN2) [91-94], and muscle myogenesis and hyperthrophy ( DACT1, DIO2, RPTOR , and PLEKHM3) [95-99] These proteins were also negatively correlated with CpGs located in genes such as KCNMA1, NOTCH1 , and CAMKK2 which are involved in skeletal muscle regeneration, proliferation and differentiation [100-105], DHRS3, DGKG, LPIN1, WNT5A which have been associated with obesity, metabolic syndrome and lipid regulation [106-108], LRRC2 which is a mediator of mitochondrial and cardiac function [109], and PDE4A which has been associated with diabetes [110; 111]. Based on results of this integration, we suggest that future work studying the relationship between such genes/proteins should be prioritized as this may reveal important mechanisms associated with exercise response across multiple OMIC layers.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation and proteomics integration uncover dose-dependent group and individual responses to exercise in human skeletal muscle

Michaux

Landen

Alvarez-Romero

et al. 2022

Preprint

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Objective: Exercise is a major regulator of muscle metabolism, and health benefits acquired by exercise are a result of molecular shifts occurring across multiple OMIC levels (i.e. epigenome, transcriptome, proteome). Identifying robust targets associated with exercise response, at both group and individual levels, is therefore important to develop health guidelines and targeted health interventions. Methods: Twenty, apparently healthy, moderately trained (VO2 max= 51.0 sd= 10.6 mL/min/kg) males (age range= 18-45yrs) from the Gene SMART (Skeletal Muscle Adaptive Responses to Training) study completed a 12-week High-Intensity Interval Training (HIIT) intervention. Muscle biopsies were collected at baseline and after 4, 8, and 12 weeks of HIIT. High throughput DNA methylation (~850 CpG sites), and proteomic (~3000 proteins) analyses were conducted at all-time points. Mixed-models were applied to estimate group and individual changes, and methylome and proteome integration was conducted using a holistic multilevel approach with the mixOmics package. Results: Significant shifts in the methylome (residual analysis) and proteome profiles were observed after 12 weeks of HIIT. 461 proteins significantly changed over time (at 4, 8, and 12 weeks), whilst only one differentially methylated position (DMP) was changed (adj.p-value <0.05). K-means analysis revealed clear protein clustering exhibiting similar changes over time. Individual responses to training were observed in 101 proteins. Seven proteins had a large effect-sizes >0.5, among them are two novel exercise- related proteins, LYRM7 and EPN1. Integration analysis uncovered bidirectional relationships between the methylome and proteome. Conclusions: We showed a significant influence of HIIT on the epigenome and proteome in human muscle, and uncovered groups of proteins clustering according to similar patterns across the exercise intervention. Individual responses to exercise were observed in the proteome with novel mitochondrial and metabolic proteins consistently changed across individuals. Future work is required to elucidate the role of such proteins in response to exercise as well as to investigate the mechanisms associating genes and proteins in response to exercise.

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Phosphodiesterase 4 inhibition restrains muscle proteolysis in diabetic rats by activating PKA and EPAC/Akt effectors and inhibiting FoxO factors

Cited by 8 publications

References 38 publications

PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson’s disease in rats

PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson’s disease in rats

Methylome and proteome integration in human skeletal muscle uncover group and individual responses to high‐intensity interval training

DNA methylation and proteomics integration uncover dose-dependent group and individual responses to exercise in human skeletal muscle

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