Pharmacologic approaches to prevent skeletal muscle atrophy after spinal cord injury

Otzel, Dana M.; Kok, Hui Jean; Graham, Zachary A.; Barton, Elisabeth R.; Yarrow, Joshua F.

doi:10.1016/j.coph.2021.07.023

Cited by 15 publications

(7 citation statements)

References 48 publications

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“…However, there is still debate on the role of natural products in skeletal muscle health (Qu et al, 2021). Although these natural substances have shown promise in preclinical research, it is yet unknown if they are clinically effective and safe (Otzel et al, 2021). In clinical studies, therapeutic interventions including etanercept (TNFα inhibitor) and neutralizing antibody infliximab that blocks TNFα had no success to treat muscle wasting induced by cachexia (Wiedenmann et al, 2008;Wu et al, 2013), while they have shown promising results in inflammatory muscle loss induced by RA and Crohn's disease (Chen et al, 2013;Subramaniam et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Skeletal muscle atrophy is characterized by the decrease in muscle mass, strength and/or physical performance, increasing the likelihood of adverse outcomes, including frailty, fall-related fractures, physical disability, social exclusion, hospitalization, ultimately increased health care costs and mortality (Lin et al, 2022). No drugs are currently approved to counter muscle atrophy (Otzel et al, 2021). Physical activity and nutritional supplementation are the two major interventions actively implemented in clinical settings, but the effects are limited and the compliance is poor (Chhetri et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation

Tao

Qian

et al. 2022

Front. Pharmacol.

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No drug options exist for skeletal muscle atrophy in clinical, which poses a huge socio-economic burden, making development on drug interventions a general wellbeing need. Patients with a variety of pathologic conditions associated with skeletal muscle atrophy have systemically elevated inflammatory factors. Morroniside, derived from medicinal herb Cornus officinalis, possesses anti-inflammatory effect. However, whether and how morroniside combat muscle atrophy remain unknown. Here, we identified crucial genetic associations between TNFα/NF-κB pathway and grip strength based on population using 377,807 European participants from the United Kingdom Biobank dataset. Denervation increased TNFα in atrophying skeletal muscles, which inhibited myotube formation in vitro. Notably, morroniside treatment rescued TNFα-induced myotube atrophy in vitro and impeded skeletal muscle atrophy in vivo, resulting in increased body/muscles weights, No. of satellite cells, size of type IIA, IIX and IIB myofibers, and percentage of type IIA myofibers in denervated mice. Mechanistically, in vitro and/or in vivo studies demonstrated that morroniside could not only inhibit canonical and non-canonical NF-κB, inflammatory mediators (IL6, IL-1b, CRP, NIRP3, PTGS2, TNFα), but also down-regulate protein degradation signals (Follistatin, Myostatin, ALK4/5/7, Smad7/3), ubiquitin-proteasome molecules (FoxO3, Atrogin-1, MuRF1), autophagy-lysosomal molecules (Bnip3, LC3A, and LC3B), while promoting protein synthesis signals (IGF-1/IGF-1R/IRS-1/PI3K/Akt, and BMP14/BMPR2/ALK2/3/Smad5/9). Moreover, morroniside had no obvious liver and kidney toxicity. This human genetic, cells and mice pathological evidence indicates that morroniside is an efficacious and safe inflammatory muscle atrophy treatment and suggests its translational potential on muscle wasting.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation

Tao

Qian

et al. 2022

Front. Pharmacol.

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“…This article is a US Government work. It is not subject to copyright under 17 105 and is also made available for use under a CC0 license.…”

Section: Authormentioning

confidence: 99%

“…Muscle mass can be maintained or increased after SCI using interventions that load muscle, such as neuromuscular electrical stimulation/functional electrical stimulation [NMES/FES; (12)(13)(14)(15)] or body-weight supported treadmill training (16). Molecular interventions have shown little efficacy in preserving muscle mass to sham control levels in pre-clinical models of severe and complete SCI (17) even when muscle is exposed to potent stimuli such as FES, testosterone, or the combination of the two (18). However, these interventions have led to 7-15% increases in muscle mass compared to SCI-only controls, though the response varies based on the muscle (18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Assessing the impact of boldine on the gastrocnemius using multiomic profiling at 7 and 28 days post-complete spinal cord injury in young male mice

Potter¹,

Toro

Harlow³

et al. 2022

Preprint

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Spinal cord injury (SCI) results in rapid muscle loss. The mechanisms of muscle atrophy have been well-described but there is limited information specific to SCI. Exogenous molecular interventions to slow muscle atrophy in severe-to-complete SCI have been relatively ineffective and the wide-ranging physiologic response to SCI requires the search for novel therapeutic targets. Connexin hemichannels (CxHC) allow non-selective passage of small molecules into and out of the cell. Boldine, a CxHC-inhibiting aporphine found in the boldo tree (Peumus boldus), has shown promising pre-clinical results in slowing atrophy during sepsis and dysferlinopathy. We administered 50 mg/kg/d of boldine to spinal cord transected mice beginning at day 3 post-injury. Tissue was collected 7 and 28 d post-injury and the gastrocnemius used for multiomic profiling. Boldine did not prevent body or muscle mass loss but attenuatee SCI-induced changes in the abundance of proline, phenylalanine, leucine and isoleucine, as well as glucose, 7 d post-SCI. SCI resulted in the differential expression of ~7,700 and ~2,000 genes at 7 and 28 d, respectively, compared to sham animals, with enrichment for pathways associated with ribosome biogenesis, translation and oxidative phosphorylation. Boldine altered the expression of ~150 genes at 7 d and ~110 genes at 28 d post-SCI. Methylation analyses highlighted distinct patterns at both 7 and 28 d following SCI both with and without boldine. Taken together, boldine is not an efficacious therapy to preserve body and muscle mass after complete SCI, though it preserved or attenuated SCI-induced changes across the metabolome, transcriptome and methylome.

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“…The skeletal muscle is also a highly plastic organ. The skeletal muscle mass decreases with immobilization, malnutrition, and injury [ 1 , 2 , 3 ]. Diseases such as cancers, cardiovascular diseases, neurodegenerative diseases, chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD) reduce skeletal muscle mass [ 4 , 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

The Functional Role of Long Non-Coding RNA in Myogenesis and Skeletal Muscle Atrophy

Hitachi

Honda

Tsuchida

2022

Cells

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Skeletal muscle is a pivotal organ in humans that maintains locomotion and homeostasis. Muscle atrophy caused by sarcopenia and cachexia, which results in reduced muscle mass and impaired skeletal muscle function, is a serious health condition that decreases life longevity in humans. Recent studies have revealed the molecular mechanisms by which long non-coding RNAs (lncRNAs) regulate skeletal muscle mass and function through transcriptional regulation, fiber-type switching, and skeletal muscle cell proliferation. In addition, lncRNAs function as natural inhibitors of microRNAs and induce muscle hypertrophy or atrophy. Intriguingly, muscle atrophy modifies the expression of thousands of lncRNAs. Therefore, although their exact functions have not yet been fully elucidated, various novel lncRNAs associated with muscle atrophy have been identified. Here, we comprehensively review recent knowledge on the regulatory roles of lncRNAs in skeletal muscle atrophy. In addition, we discuss the issues and possibilities of targeting lncRNAs as a treatment for skeletal muscle atrophy and muscle wasting disorders in humans.

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Pharmacologic approaches to prevent skeletal muscle atrophy after spinal cord injury

Cited by 15 publications

References 48 publications

Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation

Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation

Assessing the impact of boldine on the gastrocnemius using multiomic profiling at 7 and 28 days post-complete spinal cord injury in young male mice

The Functional Role of Long Non-Coding RNA in Myogenesis and Skeletal Muscle Atrophy

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