Pharmacological effects of denervated muscle atrophy due to metabolic imbalance in different periods

Introduction

As a pivotal effector organ within the peripheral nervous system, the structural integrity and functional preservation of skeletal muscle are subject to control and regulation by the nervous system. Peripheral nerve injury arising from acute trauma results in the loss of innervation from skeletal muscle. This initiates a sequence of pathological changes, including reduced muscle fiber cross-sectional area, myofibril degradation with destruction of sarcomeres, diminished contraction speed, and fibrosis, ultimately culminating atrophy (Dumitru et al., 2018). The regeneration rate of peripheral nerves is slow after injury. As a result, the target muscles of severe patients become irreversibly atrophied before being re-innervated by the nerves. This can even lead to disabling in the patients, bringing a heavy burden to the family and society (Gu et al., 2011). Therefore, a series of problems in target muscle repair and functional reconstruction after peripheral nerve injury could be resolved by exploring novel and effective methods for the treatment of skeletal muscle atrophy.

Skeletal muscle atrophies upon innervation loss due to perturbations in the balance between protein synthesis and degradation. Notably, protein degradation pathways become activated, while protein synthesis pathways are repressed, constituting the underlying cause of skeletal muscle atrophy. Effective alleviation of skeletal muscle atrophy is promoted by inhibition of protein degradation and stimulation of protein synthesis (Lang et al., 2017; Li et al., 2017; Cui et al., 2019). Several molecules are involved in the process of denervated muscular atrophy, and the mechanism of regulating denervated muscular atrophy is also extremely complicated. Recent years have witnessed many studies on denervated muscular atrophy at home and abroad, but most of these studies have focused on a single event, a single gene or protein (Castets et al., 2019; Janice Sanchez et al., 2019). A more comprehensive understanding of the denervated skeletal muscle atrophy process is attainable by elucidating pivotal regulators and therapeutic targets. Shen et al. (2019) employed microarray analysis to scrutinize target muscles at varying post-denervation time points, revealing that the 28-day period following a neural injury can be segmented into four distinct transcriptional phases, demarcated by three nodal transitions (Shen et al., 2019). These phases encompass the oxidative stress stage, inflammation stage, atrophy stage, and atrophic fibrosis stage. Consistent with previous research, the phenotype of skeletal muscle atrophy manifests between 36 h and 3 days, aligning with the aforementioned atrophy period (Shen et al., 2019; Qiu et al., 2021). Consequently, these research findings facilitate more optimal utilization of diverse methods for denervated skeletal muscle atrophy treatment. Several treatment modalities are currently proposed, encompassing electrical stimulation (Dow et al., 2005; Tamaki et al., 2017) and noncoding RNA (He et al., 2016; Li et al., 2017; Hitachi et al., 2019). Furthermore, extensive utilization of various food and drug extracts is evident in the treatment of denervated skeletal muscle atrophy.

The enhanced medical application of traditional Chinese medicine (TCM) is attributed to its multifaceted functionalities and its facile interaction with substances within the human body. Substantial strides have been made in studying the prevention and treatment of skeletal muscle atrophy using various drugs. Noteworthy achievements include effective myotube atrophy management through triptolide, an ingredient isolated from ancient Chinese herbal medicine. This agent triggers IRS-1 degradation and activates the FOXO3 pathway activation (Wang et al., 2020). Furthermore, withaferin A (WFA), a natural protein-specific binding waveform, mitigates nuclear factor kappa B (NF-κB)-mediated pro-inflammatory signaling, thereby alleviating cancer cachexia-induced skeletal muscle atrophy (Straughn and Kakar, 2019). This article highlights distinct stages of skeletal muscle atrophy, protein synthesis pathways, and other pathways. It systematically summarizes the role of food and drug extracts and other effects on the treatment of skeletal muscle atrophy, which can provide a reference for the clinical management of denervated skeletal muscle atrophy.

Drugs that Play a Protective Role by Inhibiting Protein Degradation

Inhibition of reactive oxygen species

An earlier study involving rats subjected to neural exchange suggested that heightened mitochondrial permeability transitions and increased apoptosis result in elevated mitochondrial ROS production, signifying mitochondrial dysfunction following denervation (Adhihetty et al., 2007). Reactive oxygen species (ROS) are accountable for maintaining the homeostasis of various physiological processes. A mounting body of evidence posits oxidative stress as a crucial regulator of muscle wasting (Jackman and Kandarian, 2004; Powers et al., 2005). Meanwhile, an initial stage in denervated skeletal muscle exposes aberrant ROS production. Thus, curbing excessive ROS production can ameliorate skeletal muscle atrophy. Compared to a control group, a delay in muscle atrophy mediated by ROS inhibition was reported by Kim et al. (2018). On injecting Oenothera odorata root extract (EVP) in both H2O2-treated C2C12 myoblasts and sciatic-denervated mice (Kim et al., 2018). They probed deeper into the mechanistic underpinnings of how reactive oxygen species oversee skeletal muscle atrophy. EVP suppressed superoxide dismutase 1 (SOD1) expression and augmented HSP70 expression in H2O2-treated C2C12 myoblasts and sciatic-neutralized mice. In addition, EVP regulates apoptotic signals, including caspase-3, B-cell lymphoma protein 2 (Bcl-2), Bcl-2-associated X (Bax), and ceramides. Administration of recombinant heat shock protein 70 delays peripheral muscle denervation in the SOD1 (G93A) mouse model of amyotrophic lateral sclerosis (Gifondorwa et al., 2012). O’Leary and Hood have previously shown that seven days of muscle disuse increases the expression of Beclin-1, as well as LC3-II, a known component of autophagy (O’Leary and Hood, 2009). These studies provide evidence for EVP’s protective effect and regulatory mechanism on denervation muscle atrophy. The glutathione content and malondialdehyde (MDA) levels are considered indicators of oxidative stress and were assayed in the denervated gastrocnemius muscle. As a free radical scavenger, adding vitamin E can restore glutathione levels and reduce MDA levels, further confirming the conclusion that oxidative stress accelerates muscle atrophy (Demiryurek and Babul, 2004). Indeed, increased oxidative damage after denervation resulted in increased ROS production, decreased surface hydrophobicity, and decreased enzymatic activities of glyceraldehyde-3-phosphate dehydrogenase and creatine kinase, while increased mitochondrial ROS may also play a signaling role (Pierce et al., 2006). Another compelling candidate for ROS-mediated signaling is NF-κB. The involvement of NF-κB in muscle atrophy is recognized. The inhibitor of apoptosis 1 (cIAP1) protein, a positive regulator of NF-κB signaling, exhibited upregulation in denervated muscles compared to non-denervated controls 14 days post-denervation. Genetic or pharmacological inhibition of cIAP1 curtailed canonical NF-κB signaling, thus attenuating denervation-induced muscle atrophy (Lala-Tabbert et al., 2019). Furthermore, mitochondrial ROS has been demonstrated to upregulate the expression of ubiquitin ligase, atrogin-1/MAFbx, potentially contributing to atrophy through enhanced protein degradation by the 26S proteasome system (Li et al., 2005). We found that pyrroloquinoline quinone (PQQ)-mediated reduction in the expression of reactive oxygen species and inflammatory factors results in a decrease in the expression of MuRF1 and MAFbx, ultimately improving denervated skeletal muscle atrophy (Qiu et al., 2018; Ma et al., 2019). Kuo from Taiwan revealed PQQ impairs denervation-induced skeletal muscle atrophy by activating PGC-1α and integrating mitochondrial electron transport chain complexes (Kuo et al., 2015). Previous research by our team reported a reduction of denervation-induced oxidative stress and inflammation mediated by salidroside, inhibiting muscle proteolysis and ultimately alleviating muscle atrophy caused by denervation (Huang et al., 2019).

Inhibition of pro-inflammatory factors

Apigenin is a natural plant flavonoid acclaimed for its anti-obesity, anti-inflammatory, antioxidant, and anti-cancer attributes. Apigenin was attributed to dose-dependent inhibition of collagenase activity implicated in rheumatoid arthritis (RA) and the suppression of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophage cells (Lee et al., 2007). In denervated gastrocnemius and soleus muscles, apigenin treatment impeded the upregulation of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 expression (Choi et al., 2018). Furthermore, Shiota et al. (2015) reported that apigenin exerted inhibitory effects on atrogin-1/MAFbx expression and curbed the reduction in myotube diameter induced by LPS stimulation in the C2C12 murine cell line (Shiota et al., 2015).

Ficus carica L. (FCL.), a flowering plant, contains flavonoids, psoralen, and bergapten, renowned for their antioxidant, anti-inflammatory, and anti-apoptotic characteristics. They are also implicated in quelling IL-1β and IL-6 production in atrophic muscles, attenuating muscle inflammation by inhibiting nuclear factor NF-κB activation (Dai et al., 2020). A study by Aarti Yadav et al. identified quercetin as a dietary antioxidant flavonoid that curbed inflammation in myotubes, fully reinstating TNF and an a-induced reduction of myotube diameter (Kim et al., 2018). This reflects muscle morphology at the cellular level. Quercetin improves motor function and muscle mass in aged people (Yadav et al., 2022). These reported effects of flavonoids are in other skeletal muscle atrophy models rather than in denervation-induced skeletal muscle atrophy. However, apigenin, functioning as a bioactive flavone, augmented the fiber-cross sectional area by 0.1% in the gastrocnemius muscle of sciatic denervated mice over 2 weeks. The enhanced cross-sectional area was substantiated by diminished levels of TNF-α in the gastrocnemius and IL-6 in the soleus muscle (Choi et al., 2018). Buyang Huangwu Tang (BYHWT), a classic Chinese medicine formula, ameliorated the inflammatory response in denervation-dependent skeletal muscle atrophy rat models (Zhou et al., 2020). Wu et al. (2019) found that negative regulation of pro-inflammatory cytokine mediated by salidroside attenuates denervation-induced skeletal muscle atrophy. The discernible pathway involves the inflammation caused by denervation in skeletal muscle, leading to the generation of inflammatory cytokines, particularly IL-6. This, in turn, augments the phosphorylation of STAT3 and the expression of SOCS3, which consequently triggers the activation of the proteolytic pathway in the muscle. Salidroside curbed muscle proteolysis and muscle atrophy by tempering the inflammatory response triggered by innervation. This likely transpired through the inactivation of the STAT3/SOCS3 pathway (Wu et al., 2019).

Regulation of ubiquitin-proteasome and autophagy-lysosome pathway

Activation of proteolytic metabolism and inhibition of protein synthesis pathway are the primary causes of skeletal muscle atrophy following denervation. The proteolytic pathway chiefly encompasses the ubiquitin-proteasome system and the autophagy-lysosome system. Clenbuterol (CLE) is a beta-adrenergic receptor stimulant employed in treating muscle spasms and asthma (Bohorov et al., 1987; Pairet et al., 1997). In vivo and in vitro treatment with CLE was found to prohibit the transcriptional upregulation of atrophy-related Ub ligases (i.e., MAFbx and MuRF1) in denervated soleus muscles (Goncalves et al., 2012). MAFbx overexpression led to a reduction in cultured muscle cell line size, indicating accelerated protein catabolism. Conversely, MAFbx gene depletion impeded nerve transection-induced muscle loss (Bodine et al., 2001). Nandrolone decelerates denervation atrophy by repressing MAFbx and MuRF1 (Zhao et al., 2008). The results showed that Nandrolone inhibited the expression of MAFbx and MuRF1 in subacutely denervated muscles. Reduced MAFbx and MuRF1 expression 35 and 56 days after denervation, suggesting that protection against denervation atrophy is time-related. Furthermore, no decrease in MAFbx or MuRF1 expression was observed at 3, 7, 14, or 31 days when nandrolone failed to prevent denervation atrophy at these time points. This underscores a mechanistic association between lowered MAFbx or MuRF1 levels and attenuated atrophy. Irisin is a 112 amino acid glycosylated protein hormone formed by the proteolysis of FNDC5 (Schumacher et al., 2013). The pivotal role of irisin in rescuing skeletal muscle atrophy was substantiated by the significant increase in the denervated muscle mass following irisin injection. Estimating the protein levels of both MAFbx and MuRF1, it was observed that injection of irisin resulted in a marked reduction in MAFbx and MuRF1 protein levels in denervated muscle. These findings advocate that irisin treatment curbed the expression of key indicators of skeletal muscle wasting during denervation-induced muscle atrophy (Reza et al., 2017).

Phenolic compounds derived from plants deliver diverse health benefits, mitigating the risk of cardiovascular disease and cancer (Kris-Etherton et al., 2002). Moreover, the protective impact of phenolic compounds from olive oil on muscle atrophy has been validated. These compounds can also alleviate the insulin resistance of skeletal muscle induced by a high-fat diet (Fujiwara et al., 2017; Szychlinska et al., 2019). In terms of alkylresorcinols (ARs) in denervated muscle atrophy, dietary alkylresorcinol supplementation was reported to thwart muscle atrophy by restraining the expression of the related genes of the ubiquitin-proteasome and autophagy-lysosomal pathway (Hiramoto et al., 2018). This study demonstrated that AR ingestion prevented denervation-induced hindlimb muscle weight and muscle fiber size reductions. However, ubiquitin ligase and autophagy-related gene expression related to muscle proteolysis were somewhat higher in denervated mice on an ARs-supplemented diet (D-AR) compared to those on a normal diet (D-ND). Furthermore, the abundance of autophagy marker p62 was significantly higher in D-AR than in D-ND. Fish oil rich in n-3 polyunsaturated fatty acids, including eicosapentaenoic acid and docosahexaenoic acid, is known for maintaining muscle mass. However, numerous studies have underscored fish oil’s positive role in various skeletal muscle atrophy models, such as cancer cachexia (Whitehouse et al., 2001), acute starvation (Whitehouse and Tisdale, 2001), sepsis (Khal and Tisdale, 2008), arthritis (Castillero et al., 2009), hind-limb immobilization (You et al., 2010). Komiya et al. (2019) documented that fish oil regulates ubiquitin ligase transcriptional levels through the TNF-α signaling pathway but not the FOXO1 pathway. Nevertheless, dietary fish oil intake has demonstrated no significant effect on skeletal muscle mass loss induced by sciatic nerve denervation (Komiya et al., 2019). Furthermore, BYHWT treatment is also associated with decreased levels of skeletal muscle atrophy-specific molecules MAFbx and MuRF1. This finding aligns with the outcomes of inflammatory response and motor endplate alterations following BYHWT treatment (Zhou et al., 2020). NeuroHeal, a new neuroprotective drug for peripheral nerve injury, discovered using artificial intelligence is based on a combination of two approved drugs, acamprosate and ribavirin, which facilitate its preparation for clinical application. Decreased levels of MAFbX and MuRF1 proteins were evident in the NeuroHeal group in denervated muscles. Denervation-induced autophagy activation characterized by LC3II and p62/SQSTM1 levels was diminished by NeuroHeal, indicating blocked autophagy flux (Marmolejo-Martinez-Artesero et al., 2020).

Resveratrol, a natural phytochemical, is widely found in plants, fruits, and red wine (Zhu et al., 2017). Studies reveal that treatment with 0.5% of the food intake of resveratrol can alleviate muscle atrophy caused by innervation in mice. The reduction of the MAFbx-dependent system and the improvement of autophagy defects are responsible for this attenuation (Asami et al., 2018). Geranylgeraniol (GGOH), as a C20-type isoprene found in fruits, vegetables, and grains, serves as an intermediate product of the Mevalonate pathway and a precursor of Geranylgeranyl pyrophosphate (Muraguchi et al., 2011). Miyawaki et al. (2020) reported that GGOH administration increased muscle fiber size in denervation-induced skeletal muscle atrophy in vivo and curtailed denervation-induced MAFbx expression (Miyawaki et al., 2020). The inhibitory impact of GGOH on skeletal muscle atrophy could potentially be attributed to its androgen-inhibiting effects, subsequently curbing MAFbx and MuRF1 (Pires-Oliveira et al., 2010). In a hind limb unloading model, administration of quercetin to the gastrocnemius muscle curtailed MAFbx and MuRF1 expression, thereby suppressing skeletal muscle mass loss (Mukai et al., 2010). Isoflavones, natural organic compounds, inhibit denervation-induced apoptosis and muscle atrophy. Studies suggest that isoflavones can suppress MuRF1 transcriptional activity and myotube atrophy (Tabata et al., 2019).

In addition to the aforementioned roles of vitamin E in regulating reactive oxygen species during skeletal muscle atrophy, different vitamins also play significant roles in various stages of denervation-induced skeletal muscle atrophy. Vitamin C deficiency was reported to reduce muscle weight, elevate FOXO-1, MAFbx, and MuRF1 expression. Re-administration of vitamin C could restore muscle weight and lower gene expression in skeletal muscle atrophy (Takisawa et al., 2019). Vitamin D, another member of the vitamin family, participates in calcium absorption, utilization, and bone calcification. However, recent findings suggest its involvement in skeletal muscle functions in different situations. In mice, vitamin D receptor deletion resulted in reduced muscle fiber size. In experiments using C2C12 cells, vitamin D suppressed the expression of cathepsin L and MAFbx (Endo et al., 2003; Hirose et al., 2018). We have summarized the protective effects of drugs in the process of catabolism during denervated muscle atrophy in Fig. 1.

Figure 1: Overview of the effects of drugs at different stages of denervated skeletal muscle atrophy.

The Effect of Drugs on the Protein Synthesis Pathway

Possibly through activation of the adenosine monophosphate-activated protein kinase pathway, Royal jelly, comprising water, protein, sugar, and lipids, can avert the reduction in skeletal muscle fiber diameter following denervation. Treatment of C2C12 myoblasts with Royal jelly promoted differentiation and proliferation (Shirakawa et al., 2020). In the process of denervated skeletal muscle atrophy, the Notch signaling pathway is activated early after denervation and subsequently declined. Meanwhile, the effect of nandrolone on the Notch signaling ensues following nerve transection, which occurs earlier than the protective effect that prevents continued muscle loss (Liu et al., 2011). In denervated mouse models, dietary intake of 8-prenylnaringenin triggers Akt phosphorylation, thereby potentially alleviating skeletal muscle atrophy (Mukai et al., 2012).

The Effect of Drugs on Other Pathways

Due to its binding affinity to estrogen receptors (ERs), several physiological functions of genistein are attributed to its estrogenic activity (Kuiper et al., 1998). ERs are present in the skeletal muscle, and ER subtypes ER-α and ER-β have a vital role in the differentiation and inflammation of myoblasts (Ogawa et al., 2011; Velders et al., 2012). The intake of genistein exhibits a protective effect on muscle loss caused by innervation. ER-α is activated during soleus muscle atrophy. Therefore, it may be presumed that genistein targets ER-α, thereby exerting a protective effect against muscle atrophy (Aoyama et al., 2016). Nandrolone enhances strength and functional recovery in re-innervated muscles post-establishment of denervation atrophy (Isaacs et al., 2013). Studies have confirmed the efficacy of growth hormone in treating denervated skeletal muscle atrophy. In cases of peripheral nerve injury, Tuffaha et al. (2016) unveiled that growth hormone therapy could expedite axon regeneration in male rats, foster axon myelination, diminish muscle atrophy, and amplify muscle innervation. Nonetheless, further research is crucial to unveil the precise molecular mechanism (Tuffaha et al., 2016). Bortezomib retards the atrophy of rat thyroid muscle and posterior circular ganglion muscles caused by innervation, though the specific mechanism has not been clarified (Sei et al., 2015). Finally, we summarized the pharmacological protective effects mentioned in the review on denervated skeletal muscle atrophy and present them in Table 1.

Conclusion

Comprehending the intricate pathophysiological course of denervated skeletal muscle atrophy is significant in uncovering more drugs or methodologies to combat this condition. In this review, we introduced the proposition from the previous phase: denervated skeletal muscle atrophy can be categorized into four stages as a foundation and summarized various drugs reported as effective for addressing denervated skeletal muscle atrophy across different stages. Our prior investigations also highlighted the pivotal roles of salidroside, isoquercitrin, and PQQ in alleviating denervated skeletal muscle atrophy by modulating distinct signaling pathways or molecules. However, comprehensive research is imperative to ascertain the ongoing efficacy of these drugs.

Acknowledgement: The authors thank Professor Jian Xu and Rongrong Chen from Affiliated Maternity and Child Health Care Hospital of Nantong University for their valuable suggestions for this review.

Funding Statement: The present study was supported by the National Natural Science Foundation of China (Grant No. 32200940), Science and Technology Bureau of Nantong (Grant Nos. JC2020101, JC2021085), and Municipal Health Commission of Nantong (Grant No. MA2020019).

Author Contributions: The authors confirm contribution to the paper as follows: study conception and design: JIAYING QIU, YAN CHANG, HAIBO ZHANG, ZHENYU ZHANG; data collection: HUI XU, WANQING XU, QINGWEN ZHU; analysis and interpretation of results: JIAYING QIU, WENPENG LIANG, MENGSI LIN; draft manuscript preparation: JIAYING QIU, ZHENYU ZHANG; All authors reviewed the results and approved the final version of the manuscript.

Availability of Data and Materials: The research results highlighted in this review are from publicly available papers.

Ethics Approval: Not applicable.

Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present review.

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