Adverse Neurological Effects of Short-Term Sleep Deprivation in Aging Mice Are Prevented by SS31 Peptide

Wu, Jinzi; Dou, Yan; Ladiges, Warren

doi:10.3390/clockssleep2030024

Cited by 11 publications

(5 citation statements)

References 36 publications

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“…Both compounds restored the derangements observed to almost control levels except for SS-31, which could not restore the levels of the fission protein FIS1, which controls the mitochondrial inner membrane integrity and is dispensable for mitochondrial division. Although SS-31 has been shown to interact with the inner mitochondrial membrane to modulate electron flux, increase ATP generation, and decrease ROS production (67), the alteration in FIS1 due to infection appears not to be rescued by SS-31.…”

Section: Discussionmentioning

confidence: 99%

Skeletal Muscle Mitochondrial Dysfunction Mediated byPseudomonas aeruginosaQuorum Sensing Transcription Factor MvfR: Reversing Effects with Anti-MvfR and Mitochondrial-Targeted Compounds

Aggarwal,

Singh,

Chakraborty

et al. 2024

Preprint

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Sepsis and chronic infections with Pseudomonas aeruginosa, a leading ESKAPE bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine P. aeruginosa infection, we deciphered the systemic impact of the quorum sensing (QS) transcription factor MvfR by interrogating five days post-infection its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs ATP generation, oxidative phosphorylation (OXPHOS), and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR-mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Skeletal Muscle Mitochondrial Dysfunction Mediated byPseudomonas aeruginosaQuorum Sensing Transcription Factor MvfR: Reversing Effects with Anti-MvfR and Mitochondrial-Targeted Compounds

Aggarwal,

Singh,

Chakraborty

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Both compounds restored the derangements observed to almost control levels except for SS-31, which could not restore the levels of the fission protein FIS1, which controls the mitochondrial inner membrane integrity and is dispensable for mitochondrial division. Although SS-31 has been shown to interact with the inner mitochondrial membrane to modulate electron flux, increase ATP generation, and decrease ROS production ( 70 ), the alteration in FIS1 due to infection appears not to be rescued by SS-31.…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle mitochondrial dysfunction mediated by Pseudomonas aeruginosa quorum-sensing transcription factor MvfR: reversing effects with anti-MvfR and mitochondrial-targeted compounds

Aggarwal,

Singh,

Chakraborty

et al. 2024

mBio

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Sepsis and chronic infections with Pseudomonas aeruginosa , a leading “ESKAPE” bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine P. aeruginosa infection , we deciphered the systemic impact of the quorum-sensing transcription factor MvfR (multiple virulence factor regulator) by interrogating, 5 days post-infection, its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs adenosine triphosphate generation, oxidative phosphorylation, and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR-mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients. IMPORTANCE Skeletal muscle, pivotal for many functions in the human body, including breathing and protecting internal organs, contains abundant mitochondria essential for maintaining cellular homeostasis during infection. The effect of Pseudomonas aeruginosa (PA) infections on skeletal muscle remains poorly understood. Our study delves into the role of a central quorum-sensing transcription factor, multiple virulence factor regulator (MvfR), that controls the expression of multiple acute and chronic virulence functions that contribute to the pathogenicity of PA. The significance of our study lies in the role of MvfR in the metabolic perturbances linked to mitochondrial functions in skeletal muscle and the effectiveness of the novel MvfR inhibitor and the mitochondrial-targeted peptide SS-31 in alleviating the mitochondrial disturbances caused by PA in skeletal muscle. Inhibiting MvfR or interfering with its effects can be a potential therapeutic strategy to curb PA virulence.

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“…The reactive oxygen species (ROS) levels in the hippocampus of different groups were tested according to previous research ( Wu J. et al, 2020 ). Briefly, an appropriate amount of hippocampus tissues was cleaned with PBS (4°C precooling), and then tissue digestion was performed using 0.25% trypsin.…”

Section: Methodsmentioning

confidence: 99%

Research on the anti-aging mechanisms of Panax ginseng extract in mice: a gut microbiome and metabolomics approach

Lin,

Tang,

Liu

et al. 2024

Front. Pharmacol.

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Introduction: Aged-related brain damage and gut microbiome disruption are common. Research affirms that modulating the microbiota-gut-brain axis can help reduce age-related brain damage.Methods: Ginseng, esteemed in traditional Chinese medicine, is recognized for its anti-aging capabilities. However, previous Ginseng anti-aging studies have largely focused on diseased animal models. To this end, efforts were hereby made to explore the potential neuroprotective effects of fecal microbiota transplantation (FMT) from Ginseng-supplemented aged mice to those pre-treated with antibiotics.Results: As a result, FMT with specific modifications in natural aging mice improved animal weight gain, extended the telomere length, anti-oxidative stress in brain tissue, regulated the serum levels of cytokine, and balanced the proportion of Treg cells. Besides, FMT increased the abundance of beneficial bacteria of Lachnospiraceae, Dubosiella, Bacteroides, etc. and decreased the levels of potential pathogenic bacteria of Helicobacter and Lachnoclostridium in the fecal samples of natural aged mice. This revealed that FMT remarkably reshaped gut microbiome. Additionally, FMT-treated aged mice showed increased levels of metabolites of Ursolic acid, β-carotene, S-Adenosylmethionine, Spermidine, Guanosine, Celecoxib, Linoleic acid, etc., which were significantly positively correlated with critical beneficial bacteria above. Additionally, these identified critical microbiota and metabolites were mainly enriched in the pathways of Amino acid metabolism, Lipid metabolism, Nucleotide metabolism, etc. Furthermore, FMT downregulated p53/p21/Rb signaling and upregulated p16/p14, ATM/synapsin I/synaptophysin/PSD95, CREB/ERK/AKT signaling in brain damage following natural aging.Discussion: Overall, the study demonstrates that reprogramming of gut microbiota by FMT impedes brain damage in the natural aging process, possibly through the regulation of microbiota-gut-brain axis.

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Adverse Neurological Effects of Short-Term Sleep Deprivation in Aging Mice Are Prevented by SS31 Peptide

Cited by 11 publications

References 36 publications

Skeletal Muscle Mitochondrial Dysfunction Mediated byPseudomonas aeruginosaQuorum Sensing Transcription Factor MvfR: Reversing Effects with Anti-MvfR and Mitochondrial-Targeted Compounds

Skeletal Muscle Mitochondrial Dysfunction Mediated byPseudomonas aeruginosaQuorum Sensing Transcription Factor MvfR: Reversing Effects with Anti-MvfR and Mitochondrial-Targeted Compounds

Skeletal muscle mitochondrial dysfunction mediated by Pseudomonas aeruginosa quorum-sensing transcription factor MvfR: reversing effects with anti-MvfR and mitochondrial-targeted compounds

Research on the anti-aging mechanisms of Panax ginseng extract in mice: a gut microbiome and metabolomics approach

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