MuSCs and IPCs: roles in skeletal muscle homeostasis, aging and injury.

Skeletal muscle is a highly specialized tissue composed of myofibres that performs crucial functions in movement and metabolism. In response to external stimuli and injuries, a range of stem/progenitor cells, with muscle stem cells or satellite cells (MuSCs) being the predominant cell type, are rapidly activated to repair and regenerate skeletal muscle within weeks. Under normal conditions, MuSCs remain in a quiescent state, but become proliferative and differentiate into new myofibres in response to injury. In addition to MuSCs, some interstitial progenitor cells (IPCs) such as fibro-adipogenic progenitors (FAPs), pericytes, interstitial stem cells expressing PW1 and negative for Pax7 (PICs), muscle side population cells (SPCs), CD133-positive cells and Twist2-positive cells have been identified as playing direct or indirect roles in regenerating muscle tissue. Here, we highlight the heterogeneity, molecular markers, and functional properties of these interstitial progenitor cells, and explore the role of muscle stem/progenitor cells in skeletal muscle homeostasis, aging, and muscle-related diseases. This review provides critical insights for future stem cell therapies aimed at treating muscle-related diseases.

Adult Hippocampal Neurogenesis along the Dorsoventral Axis Contributes Differentially to Environmental Enrichment Combined with Voluntary Exercise in Alleviating Chronic Inflammatory Pain in Mice.

Cognitive behavioral therapy, such as environmental enrichment combined with voluntary exercise (EE-VEx), is under active investigation as an adjunct to pharmaceutical treatment for chronic pain. However, the effectiveness and underlying mechanisms of EE-VEx remain unclear. In mice with intraplantar injection of complete Freund's adjuvant, our results revealed that EE-VEx alleviated perceptual, affective, and cognitive dimensions of chronic inflammatory pain. These effects of EE-VEx on chronic pain were contingent on the occurrence of adult neurogenesis in the dentate gyrus in a functionally dissociated manner along the dorsoventral axis: neurogenesis in the ventral dentate gyrus participated in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas neurogenesis in the dorsal dentate gyrus was involved in EE-VEx's cognitive-enhancing effects. Chronic inflammatory pain was accompanied by decreased levels of brain-derived neurotrophic factor (BDNF) in the dentate gyrus, which were reversed by EE-VEx. Overexpression of BDNF in the dentate gyrus mimicked the effects of EE-VEx. Our results demonstrate distinct contribution of adult hippocampal neurogenesis along the dorsoventral axis to EE-VEx's beneficial effects on different dimensions of chronic pain.SIGNIFICANCE STATEMENT Environmental enrichment combined with voluntary exercise (EE-VEx) is under active investigation as an adjunct to pharmaceutical treatment for chronic pain, but its effectiveness and underlying mechanisms remain unclear. In a mouse model of inflammatory pain, the present study demonstrates that the beneficial effects of EE-VEx on chronic pain depend on adult neurogenesis with a dorsoventral dissociation along the hippocampal axis. Adult neurogenesis in the ventral dentate gyrus participates in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas that in the dorsal pole is involved in EE-VEx's cognitive-enhancing effects in chronic pain.

Nutritional Strategies for Muscle Atrophy: Current Evidence and Underlying Mechanisms.

Skeletal muscle can undergo detrimental changes in various diseases, leading to muscle dysfunction and atrophy, thus severely affecting people's lives. Along with exercise, there is a growing interest in the potential of nutritional support against muscle atrophy. This review provides a brief overview of the molecular mechanisms driving skeletal muscle atrophy and summarizes recent advances in nutritional interventions for preventing and treating muscle atrophy. The nutritional supplements include amino acids and their derivatives (such as leucine, ß-hydroxy, ß-methylbutyrate, and creatine), various antioxidant supplements (like Coenzyme Q10 and mitoquinone, resveratrol, curcumin, quercetin, Omega 3 fatty acids), minerals (such as magnesium and selenium), and vitamins (such as vitamin B, vitamin C, vitamin D, and vitamin E), as well as probiotics and prebiotics (like Lactobacillus, Bifidobacterium, and 1-kestose). Furthermore, the study discusses the impact of a combined approach involving nutritional support and physical therapy to prevent muscle atrophy, suggests appropriate multi-nutritional and multi-modal interventions based on individual conditions to optimize treatment outcomes, and enhances the recovery of muscle function for patients. By understanding the molecular mechanisms behind skeletal muscle atrophy and implementing appropriate interventions, it is possible to enhance the recovery of muscle function and improve patients' quality of life.

The TGR5 Agonist INT-777 Promotes Peripheral Nerve Regeneration by Activating cAMP-dependent Protein Kinase A in Schwann Cells.

Schwann cell (SC) myelination is a pivotal event in the normal physiological functioning of the peripheral nervous system (PNS), where myelination is finely controlled by a series of factors within SCs to ensure timely onset and correct myelin thickness for saltatory conduction. Among these, cyclic AMP (cAMP) is a promising factor for driving myelin gene expression in SCs. It has been shown that TGR5 activation is often associated with increased production of cAMP. Therefore, we speculated that the G-protein-coupled receptor (TGR5) might be involved in the PNS myelination. To test this hypothesis, sciatic nerve crush-injured mice were treated with INT-777, a specific agonist of TGR5, which significantly improved remyelination and functional recovery. Furthermore, rats that underwent sciatic nerve transection were treated with INT-777, which also promoted nerve regeneration and functional recovery. In primary SCs, the stimulatory effect of INT-777 on myelin gene expression was largely counteracted by H89, a potent inhibitor of cAMP-dependent protein kinase A (PKA). Additionally, INT-777 stimulated cell migration was blunted in the presence of H89. Overall, these data indicate that INT-777 is capable of promoting peripheral nerve regeneration and functional recovery after injury, and these benefits are likely due to the activation of the TGR5/cAMP/PKA axis. As such, INT-777, together with other TGR5 agonists, may hold great therapeutic potential for treating peripheral nerve injury.

Transcriptional Control of Peripheral Nerve Regeneration.

Transcription factors are master regulators of various cellular processes under diverse physiological and pathological conditions. Many transcription factors that are differentially expressed after injury to peripheral nerves play important roles in nerve regeneration. Considering that rapid and timely regrowth of injured axons is a prerequisite for successful target reinnervation, here, we compile transcription factors that mediates axon elongation, including axon growth suppressor Klf4 and axon growth promoters c-Myc, Sox11, STAT3, Atf3, c-Jun, Smad1, C/EBPδ, and p53. Besides neuronal changes, Schwann cell phenotype modulation is also critical for nerve regeneration. The activation of Schwann cells at early time points post injury provides a permissive microenvironment whereas the re-differentiation of Schwann cells at later time points supports myelin sheath formation. Hence, c-Jun and Sox2, two critical drivers for Schwann cell reprogramming, as well as Krox-20 and Sox10, two essential regulators of Schwann cell myelination, are reviewed. These transcription factors may serve as promising targets for promoting the functional recovery of injured peripheral nerves.

Characterization of circular RNAs in dorsal root ganglia after central and peripheral axon injuries.

In central nervous system, axons fail to regenerate after injury while in peripheral nervous system, axons retain certain regenerative ability. Dorsal root ganglion (DRG) neuron has an ascending central axon branch and a descending peripheral axon branch stemming from one single axon and serves as a suitable model for the comparison of growth competence following central and peripheral axon injuries. Molecular alterations underpin different injury responses of DRG branches have been investigated from many aspects, such as coding gene expression, chromatin accessibility, and histone acetylation. However, changes of circular RNAs are poorly characterized. In the present study, we comprehensively investigate circular RNA expressions in DRGs after rat central and peripheral axon injuries using sequencing analysis and identify a total of 33 differentially expressed circular RNAs after central branch injury as well as 55 differentially expressed circular RNAs after peripheral branch injury. Functional enrichment of host genes of differentially expressed circular RNAs demonstrate the participation of Hippo signaling pathway and Notch signaling pathway after both central and peripheral axon injuries. Circular RNA changes after central axon injury are also linked with apoptosis and cellular junction while changes after peripheral axon injury are associated with metabolism and PTEN-related pathways. Altogether, the present study offers a systematic evaluation of alterations of circular RNAs in rat DRGs following injuries to the central and peripheral axon branches and contributes to the deciphering of essential biological activities and mechanisms behind successful nerve regeneration.

Integrated analyses reveal evolutionarily conserved and specific injury response genes in dorsal root ganglion.

Rodent dorsal root ganglion (DRG) is widely used for studying axonal injury. Extensive studies have explored genome-wide profiles on rodent DRGs under peripheral nerve insults. However, systematic integration and exploration of these data still be limited. Herein, we re-analyzed 21 RNA-seq datasets and presented a web-based resource (DRGProfile). We identified 53 evolutionarily conserved injury response genes, including well-known injury genes (Atf3, Npy and Gal) and less-studied transcriptional factors (Arid5a, Csrnp1, Zfp367). Notably, we identified species-preference injury response candidates (e.g. Gpr151, Lipn, Anxa10 in mice; Crisp3, Csrp3, Vip, Hamp in rats). Temporal profile analysis reveals expression patterns of genes related to pre-regenerative and regenerating states. Finally, we found a large sex difference in response to sciatic nerve injury, and identified four male-specific markers (Uty, Eif2s3y, Kdm5d, Ddx3y) expressed in DRG. Our study provides a comprehensive integrated landscape for expression change in DRG upon injury which will greatly contribute to the neuroscience community.

Inflammation: Roles in Skeletal Muscle Atrophy.

Various diseases can cause skeletal muscle atrophy, usually accompanied by inflammation, mitochondrial dysfunction, apoptosis, decreased protein synthesis, and enhanced proteolysis. The underlying mechanism of inflammation in skeletal muscle atrophy is extremely complex and has not been fully elucidated, thus hindering the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy. In this review, we elaborate on protein degradation pathways, including the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), the calpain and caspase pathways, the insulin growth factor 1/Akt protein synthesis pathway, myostatin, and muscle satellite cells, in the process of muscle atrophy. Under an inflammatory environment, various pro-inflammatory cytokines directly act on nuclear factor-κB, p38MAPK, and JAK/STAT pathways through the corresponding receptors, and then are involved in muscle atrophy. Inflammation can also indirectly trigger skeletal muscle atrophy by changing the metabolic state of other tissues or cells. This paper explores the changes in the hypothalamic-pituitary-adrenal axis and fat metabolism under inflammatory conditions as well as their effects on skeletal muscle. Moreover, this paper also reviews various signaling pathways related to muscle atrophy under inflammatory conditions, such as cachexia, sepsis, type 2 diabetes mellitus, obesity, chronic obstructive pulmonary disease, chronic kidney disease, and nerve injury. Finally, this paper summarizes anti-amyotrophic drugs and their therapeutic targets for inflammation in recent years. Overall, inflammation is a key factor causing skeletal muscle atrophy, and anti-inflammation might be an effective strategy for the treatment of skeletal muscle atrophy. Various inflammatory factors and their downstream pathways are considered promising targets for the treatment and prevention of skeletal muscle atrophy.

Protective effect of Achyranthes bidentata polypeptides on NMDA-mediated injury is developmentally regulated via modulating NR2A and NR2B differentially.

BACKGROUND: Achyranthes bidentata polypeptides (ABPPs) are a potent intervention for excitotoxicity-related disorders such as Parkinson's disease and ischemic stroke. Previous work suggests that overstimulation of N-methyl-D-aspartate (NMDA) receptors plays a critical role in excitotoxicity, and expression of NR2 subunit variations is developmentally regulated. Our current study focused on neuroprotection of ABPPs on cultured neurons by modulation of NR2A and NR2B differentially. METHODS: Primary cultured neurons were treated with NVP-AAM077, Ro-256981, ABPPs, and then the neurons were exposed to NMDA to induce excitotoxicity. Cellular viability was detected promptly and 24-hour after exposure to NMDA by MTT assay. Patch-clamp recording was applied to evaluate the effect of ABPPs on NMDA-evoked current and the differential modulation of ABPPs on NR2A and NR2B subunits in conjunction with NVP-AAM077 and Ro-256981. RESULTS: ABPPs (10 µg/mL) blocked neuronal injury by NMDA in mature cultures, and the peptides conferred neuroprotection in immature cultures unless co-applied with NVP-AAM077. Furthermore, ABPPs enhanced NMDA current in mature cultures, while decreasing NMDA current in immature cultures. On the other hand, we showed that ABPPs increased NMDA current when Ro-256981 was present and decreased NMDA current when NVP-AAM007 was present. CONCLUSIONS: Neuroprotection of ABPPs on NMDA-mediated injury differentially in immature and mature cultures involves enhancement of NR2A subunits and prevention of NR2B subunits, indicating that dosage of ABPP should be considered in treatment with patients at different developmental stages.

A Context-Based Analgesia Model in Rats: Involvement of Prefrontal Cortex.

Cognition and pain share common neural substrates and interact reciprocally: chronic pain compromises cognitive performance, whereas cognitive processes modulate pain perception. In the present study, we established a non-drug-dependent rat model of context-based analgesia, where two different contexts (dark and bright) were matched with a high (52°C) or low (48°C) temperature in the hot-plate test during training. Before and after training, we set the temperature to the high level in both contexts. Rats showed longer paw licking latencies in trials with the context originally matched to a low temperature than those to a high temperature, indicating successful establishment of a context-based analgesic effect in rats. This effect was blocked by intraperitoneal injection of naloxone (an opioid receptor antagonist) before the probe. The context-based analgesic effect also disappeared after optogenetic activation or inhibition of the bilateral infralimbic or prelimbic sub-region of the prefrontal cortex. In brief, we established a context-based, non-drug dependent, placebo-like analgesia model in the rat. This model provides a new and useful tool for investigating the cognitive modulation of pain.

Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.

Transient receptor potential vanilloid 1 (TRPV1) receptors are expressed in nociceptive neurons of rat dorsal root ganglions (DRGs) and mediate inflammatory pain. Nonspecific inhibition of protein-tyrosine phosphatases (PTPs) increases the tyrosine phosphorylation of TRPV1 and sensitizes TRPV1. However, less is known about tyrosine phosphorylation's implication in inflammatory pain, compared with that of serine/threonine phosphorylation. Src homology 2 domain-containing tyrosine phosphatase 1 (Shp-1) is a key phosphatase dephosphorylating TRPV1. In this study, we reported that Shp-1 colocalized with and bound to TRPV1 in nociceptive DRG neurons. Shp-1 inhibitors, including sodium stibogluconate and PTP inhibitor III, sensitized TRPV1 in cultured DRG neurons. In naive rats, intrathecal injection of Shp-1 inhibitors increased both TRPV1 and tyrosine-phosphorylated TRPV1 in DRGs and induced thermal hyperalgesia, which was abolished by pretreatment with TRPV1 antagonists capsazepine, BCTC, or AMG9810. Complete Freund's adjuvant (CFA)-induced inflammatory pain in rats significantly increased the expression of Shp-1, TRPV1, and tyrosine-phosphorylated TRPV1, as well as the colocalization of Shp-1 and TRPV1 in DRGs. Intrathecal injection of sodium stibogluconate aggravated CFA-induced inflammatory pain, whereas Shp-1 overexpression in DRG neurons alleviated it. These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.