Neuromuscular degeneration plays an important role in the occurrence and development of sarcopenia, and is mainly characterized by motor unit remodeling and neuromuscular junction degeneration [22, 23]. The motor unit is composed of $\alpha$ motor neurons in the anterior horn of the spinal cord and of the skeletal muscle fibers innervated by them. In the aging process, the progressive decrease of $\alpha$ motor neurons leads to denervation of muscle fibers, and the remaining motor neurons send out collaterals for reinnervation [24, 25]. When the nerve reinnervation is not enough to compensate for the damage caused by denervation, the patient experiences muscle atrophy and hypofunction. Satellite cells are muscle-derived stem cells with proliferation abilities in the skeletal muscle, and they play an important role in muscle regeneration and damage repair [26]. In the aging process, atrophy is more pronounced in type II muscle fiber than in type I muscle fiber [27]. Moreover, the number of type II muscle fiber satellite cells decreases with increasing age, and the remaining cells have reduced regeneration and repair functions, which further aggravates the muscle fiber atrophy after denervation and causes a reduction in muscle volume [28, 29]. As a chemical synapse, the neuromuscular junction can convert the electrical impulse of the motor nerve into a muscle contraction. The neuromuscular junction also undergoes a variety of morphological and functional changes during the aging process, including a decrease in the number of acetylcholine receptors, fragmentation of the endplate, and a decrease in the number of postsynaptic folds, which together ultimately causes the failure of neuromuscular junction transmission [30]. More importantly, the instability of the neuromuscular junction structure and function is an important cause of sarcopenia (Fig. 2) [31].

Fig. 2.

Schematic representation of the main factors involved in the progression of sarcopenia. AChRs, acetylcholine receptors; GH, growth hormone; IGF-1, insulin-like growth factor-1; IL-1, interleukin 1; IL-6, interleukin 6; NMJ, neuromuscular junction; TNF-$\alpha$, tumor necrosis factor-alpha.

Although the exact pathogenesis of sarcopenia is still unclear, mitochondrial dysfunction, especially impairments in the mitochondrial quality control (MQC) pathway, plays a major role in the course of sarcopenia [32, 33]. MQC is defined by mitophagy and mitochondrial biogenesis, a mechanism that maintains mitochondrial morphology and function through mitochondrial fusion/fission [34, 35]. Mitochondrial fusion can redistribute protein and mitochondrial DNA, exchanging material and energy to meet the body’s needs [36]. Alternatively, fusion can reduce the concentration of damaged substances to maintain the normal functions of the mitochondria [37]. Fission can isolate severely damaged mitochondria and clear them through autophagy to avoid excessive accumulation of dysfunctional mitochondria and reduce the generation of reactive oxygen species (ROS) [38]. Mitochondria form a complex mitochondrial network through continuous fusion and fission (i.e., mitochondrial dynamics), which plays an important role in maintaining muscle morphology and contraction function [39]. With the appearance of aging, the MQC pathway appears abnormal, displaying disturbed mitochondrial dynamics, decreased mitophagy, and reduced mitochondrial biogenesis [40, 41, 42, 43]. Unbalanced mitochondrial dynamics and reduced mitophagy cause mitochondrial dysfunction, damage the mitochondrial network, and ultimately lead to skeletal muscle loss and muscle function decline [39]. At the same time, dysfunctional mitochondria continue to accumulate, leading to reduced adenosine triphosphate production and excessive ROS production. In turn, the increased production of ROS causes electron transport chain damage and mitochondrial DNA mutations, and then further aggravates mitochondrial dysfunction, forming a vicious circle, which finally results in the deterioration of skeletal muscle quality and function [33, 44]. On the other hand, excessive ROS reduces the sensitivity of the anabolic signaling pathway mediated by insulin-like growth factor-1 (IGF-1) and activates skeletal muscle proteolytic signaling pathways, which cause decreased muscle protein synthesis and increased protein breakdown. These changes ultimately promote the occurrence and development of sarcopenia [45, 46, 47]. In addition, mitochondrial dysfunction can cause neuromuscular junction remodeling and the loss of motor units [48]. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1$\alpha$) is an important regulator of mitochondrial biogenesis, which promotes mitochondrial biogenesis and quality control by regulating downstream transcription factors [49]. The overexpression of PGC-1$\alpha$ can prevent muscle atrophy, whereas knocking out PGC-1$\alpha$ leads to decreased muscle mass and function [50, 51]. The expression of PGC-1$\alpha$ in the skeletal muscle is significantly reduced as one ages, which may be an important cause of sarcopenia [52].

In the process of aging, patients often have low-grade, systemic chronic inflammation without corresponding clinical symptoms: that is, “inflammaging” [53]. These inflammatory factors include but are not limited to tumor necrosis factor-alpha (TNF-$\alpha$), interleukin 6 (IL-6), interleukin 1 (IL-1), TNF-$\alpha$ like weak inducer of apoptosis (TWEAK), and C-reactive protein [54, 55]. Cross-sectional studies have shown that increased levels of inflammatory cytokines, especially TNF-$\alpha$ and TWEAK, are positively correlated with both the severity and risk of sarcopenia in elderly patients, further indicating that chronic inflammation may be involved in the occurrence and development of sarcopenia [54]. TNF-$\alpha$ can activate the ubiquitin-proteasome pathway (the main pathway of skeletal muscle protein degradation) through nuclear factor-$\kappa$B (NF-$\kappa$B) to increase Muscle Ring Finger 1 expression and can lead to atrokin-1 expression independent of NF-$\kappa$B activation [56]. Inflammatory cytokines can also antagonize the effects of protein synthesis caused by IGF-1. The increased degradation and decreased synthesis of skeletal muscle protein ultimately leads to the destruction of protein homeostasis and muscle atrophy. Inflammatory cytokines can also reduce the regeneration function of muscle satellite cells, further promoting the development of sarcopenia [57]. There is also a proposed role of the relationship between inflammation and mitochondria in sarcopenia. Inflammatory cytokines cause mitochondria to produce excessive ROS, decrease the expression of PGC-1$\alpha$, damage the electron transport chain, and inhibit mitophagy, eventually leading to MQC derangements, aggravating the impairment of muscle mass and strength [58, 59, 60, 61].

Currently, sarcopenic obesity is defined as the coexistence of obesity and sarcopenia [62]. However, the pathogenesis of sarcopenic obesity is not a simple superposition of the mechanisms of these comorbidities. Obesity and sarcopenia may have some common pathogenesis and may aggravate each other [63]. In the aging process, due to the changes in hormone levels (including decreased levels of estrogen, testosterone, growth hormone, and IGF-1) and a decrease in physical activity, the resting metabolic rate is reduced, which leads to a decrease in protein synthesis and a progressive increase in fat mass [12]. The existence of sarcopenia further reduces the activity levels of elderly patients and aggravates fat accumulation [64]. Fat accumulates abnormally in adipose tissue, after which immune cells infiltrate the tissue and release a large number of pro-inflammatory cytokines, including TNF-$\alpha$, IL-6, and IL-1 [65]. These inflammatory molecules enter the circulatory system to cause systemic inflammation and promote inflammaging [63]. Excess fatty acids can also accumulate ectopic lipids in skeletal muscle, attracting immune cells that infiltrate the muscles and produce local inflammation, leading to muscle dysfunction [66]. Additionally, lipids and their derivatives in muscle cells further reduce the mitochondrial $\beta$-oxidation capacity and increase the production of ROS, causing lipotoxicity and thereby reducing muscle strength [32, 67, 68]. Intramyocellular fat accumulation and subsequent mitochondrial dysfunction lead to skeletal muscle insulin resistance, further interfere with the metabolic homeostasis of skeletal muscle, and promote muscle breakdown [69, 70].

Sarcopenia is associated with falls, disability, longer hospital stays, and mortality in the elderly, so treatment strategies should be initiated immediately when sarcopenia is diagnosed [17]. Currently, the treatment of sarcopenia mainly includes physical exercises, nutritional supplementation, and pharmacological interventions. Physical exercises are currently considered to be the most effective of these treatment options [71]. Physical exercises can significantly increase muscle mass, improving the muscle function and physical performance [72, 73]. Exercise interventions mainly include resistance training and endurance training. The current focus is mainly on resistance training. Resistance training can inhibit mitochondrial-mediated apoptosis and regulate the IGF-1/Akt/mammalian target of the rapamycin signaling pathway, thereby promoting protein synthesis [74]. A meta-analysis of 14 trials showed that there is high-quality evidence that resistance training can improve muscle mass, strength, and physical performance [75]. Importantly, high-intensity training may provide greater benefits than other exercises. An 18-month randomized controlled study involving 43 participants confirmed that high-intensity resistance exercise can increase the skeletal muscle mass and grip strength of patients with sarcopenia and can inhibit the progression of sarcopenia [76]. Endurance training can also improve mitochondrial function by increasing PGC-1$\alpha$, increase insulin sensitivity, and promote anabolism by increasing the levels of growth hormone and IGF-1 in the circulation, thus preventing and treating sarcopenia [74, 77]. However, there is no consensus on the optimal exercise frequency, intensity, or mode, which should be examined by future clinical research.

Although exercise is an effective measure with which to intervene in sarcopenia, it requires professional guidance and is often difficult for the elderly to maintain. Therefore, more and more researchers are turning their attention to nutritional interventions and pharmacological approaches. Nutritional interventions mainly include supplementation of protein, vitamin D, creatine monohydrate, and so forth. [78]. Protein and vitamin D supplementation can significantly improve muscle strength and function [79, 80]. A multicenter randomized controlled trial involving 1240 elderly people showed that vitamin D and leucine can significantly improve the muscle mass and function of patients with sarcopenia [81]. However, as the optimal dosage ranges of these nutritional supplements have not yet been determined, their clinical use has been limited. Combining exercise and nutritional supplementation is among the most promising strategies [82]. Although some trials showed that the combination is beneficial for sarcopenia, no recommendations can be proposed owing to inconsistent evidence [83]. Expert guidelines believe that the time of nutritional intake before and after exercise is critical to the increase of muscle mass [84]. Studies have found that giving nutrition after exercise can produce a good synergistic effect on muscle protein synthesis [85]. Therefore, supplementation with nutrition after exercise may be more conducive to sarcopenia. Regrettably, there is little study on the effect of nutritional intake time on sarcopenia, and some of these have not shown the benefits of supplementation with nutrition after exercise for sarcopenia. A 26-week three-arm randomized controlled trial showed that compared with whey protein pre-resistance training group, the skeletal muscle mass, functional capacity, and total strength gains of the whey protein post-resistance training group were higher, but there was no significant difference between the two groups [86]. In this regard, there is still a lack of definitive clinical evidence on the effect of nutritional intake time on sarcopenia. Further studies are still needed to provide better clinical evidence.

There are currently no drugs for the treatment of sarcopenia. Potential therapeutic drugs mainly include testosterone, selective androgen receptor modulators, and anti-inflammatory drugs [87]. Although these drugs can partially improve muscle mass and function, most of them have side effects that greatly limit their clinical usage. Studies have shown that testosterone can increase muscle protein synthesis and myogenesis, thereby improving muscle mass and strength [88, 89]. However, long-term use of testosterone may cause various complications, such as cardiovascular and prostate diseases [47, 90]. Although selective androgen receptor agonists have fewer side effects than testosterone, they have not shown significant advantages in improving muscle mass and function [91]. Therefore, testosterone is still the most effective and safest drug for sarcopenia. There is great potential for treating sarcopenia by repurposing drugs, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. A study enrolling 130 participants showed that compared with placebo, perindopril significantly improved the 6-min walking distance and physical functions of the elderly [92]. However, whether it can achieve definite curative effects in the treatment of sarcopenia still needs further verification.

With the population aging, there is an increasing demand for surgical procedures among the elderly. However, due to sarcopenia’s comorbidities, the benefits may not outweigh the complications of surgery and anesthesia for such patients, and surgery may even cause a serious decline in the quality of life. Increasing evidence indicates that sarcopenia is closely related to postoperative complications, mortality, and lengths of hospital stays [93, 94]. Fukuda et al. [95] found in a cohort study that although there was no significant difference between sarcopenia and non-sarcopenia groups in the overall incidence of complications after gastric cancer surgery, the incidence of serious complications was significantly higher in the sarcopenia group. A multivariate analysis suggests that sarcopenia is a risk factor for severe postoperative complications. In 2018, a meta-analysis of 29 studies involving 7176 patients also showed that sarcopenia is an independent predictor of an increased risk of complications after gastrointestinal tumor resection [96]. Therefore, elderly patients with sarcopenia who need surgery should attract the special attention of anesthesiologists. At present, an American Society of Anesthesiologists (ASA) classification is often used in clinical practice to assess the risk of anesthesia in perioperative patients. However, the ASA class is mainly based on the subjective judgment of the anesthesiologist, lacks relatively objective indicators, and may not be used to predict the risks of postoperative complications, mortality, and other outcomes. [97]. The combination of the ASA classification and other objective indicators can effectively assess the patient’s baseline functional status and predict perioperative risks [98]. In addition, because of the obesity characteristics of patients with sarcopenic obesity, anesthesiologists may ignore the coexisting sarcopenia and follow the guidelines for the anesthetic management of ordinary obese patients, which may lead to serious consequences. Therefore, it is particularly important to identify and diagnose sarcopenia before surgery. The 2019 expert guidelines on liver transplantation also recommend that a sarcopenia assessment should be included in the preoperative liver transplantation evaluation [99]. On one hand, preoperative sarcopenia screening can combine an ASA classification with objective indicators of sarcopenia to effectively stratify patients before surgery, guiding clinicians in decision-making and in formulating the best anesthesia plan. On the other hand, appropriate interventions (including nutrition and exercise, among others) should be carried out during the perioperative period to increase the functional reserve of a patient with sarcopenia, thereby improving the postoperative clinical course. A study showed that after a preoperative exercise and nutritional support program (i.e., prehabilitation), 4 patients in an experimental group became non-sarcopenic, and even no patients in the sarcopenia group had a higher grade of Clavien–Dindo classification or a higher incidence of postoperative complications [100]. Therefore, it is necessary to routinely perform sarcopenia screens for patients’ $\ge$60 years old or $\ge$65 years old before surgery. This can provide valuable information for anesthesiologists to use when formulating individualized management plans for patients, thereby reducing the risk of anesthesia and improving the prognosis.

Due to the existence of common pathophysiological mechanisms such as chronic inflammation and hormonal pathways, sarcopenia is an important risk factor for cognitive impairment and dementia. A meta-analysis of 22 studies found that sarcopenia is associated with an increased risk of cognitive impairment, and this effect is independent of the study population and the definitions used for sarcopenia and cognitive impairment [132]. An advanced age and preoperative cognitive impairment are both important risk factors for perioperative cognitive dysfunction [133]. Among the cognitive complications related to anesthesia, sarcopenia is closely related to the occurrence of postoperative delirium. Hiraoka et al. [134] found that the decreased muscle function group showed a higher incidence of postoperative delirium after liver cancer surgery. A retrospective cohort study of 251 patients found that compared with patients without a low skeletal muscle mass (LSMM), patients with an LSMM had a higher incidence of postoperative delirium [135]. A multivariate analysis showed that LSMM is associated with postoperative delirium in patients with colon cancer, and this correlation is more significant when patients also have malnutrition or physical dependence [135]. Therefore, patients with sarcopenia should be identified during the perioperative period, we should be vigilant about possible postoperative delirium, and we should take necessary measures to prevent postoperative delirium. Exercise and nutritional interventions are used to improve sarcopenia before surgery and reduce the occurrence of postoperative delirium. Multi-modal analgesia is used during the perioperative period to avoid postoperative delirium caused by insufficient analgesia or an overdose of opioids. If possible, the use of drugs that can cause postoperative delirium should be avoided or reduced during the perioperative period, including benzodiazepines, opioids, ketamine, antihistamines, and atropine [114].