Polyamines and Physical Activity in Musculoskeletal Diseases: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Antonino Mulè.

Autophagy dysregulation is commonplace in the pathogenesis of several invalidating diseases, such as musculoskeletal diseases. Polyamines are emerging as natural autophagy regulators with strong anti-aging effects. Recent studies indicate that spermidine reverses dysfunctional autophagy and stimulates mitophagy in muscles and heart, preventing senescence. Physical exercise, as polyamines, regulates skeletal muscle mass inducing proper autophagy and mitophagy. In addition, the combination of spermidine supplementation and regular physical exercise could have positive effects on reactivating the autophagic process flux, maintaining the skeletal muscle mass, and delaying its senescence. This suggests that exercise and spermidine may share mediators acting on similar pathways in autophagy and related processes involved in muscle maintenance. Therefore, the established geroprotective effect of spermidine supplementation and regular practice of exercise might also be promising to prevent or improve age-related musculoskeletal diseases. 

  • polyamines
  • spermine
  • spermidine
  • physical exercise
  • autophagy
  • Musculoskeletal Diseases

1. Introduction

Skeletal muscle is one of the most abundant tissues in humans. It constitutes more than 30–40% of the total body mass and extends its vital functions from posture, movement, and breathing to fundamental regulatory and metabolism functions of protein, lipid, and glucose [1]. Indeed, muscles are crucial to maintain thermogenesis and body temperature [2]. Moreover, skeletal muscles are a key site for glucose uptake from the blood and deposition as glycogen; therefore, they are targets of insulin via insulin-like growth factor 1 [3]. Some current evidence considers skeletal muscle an “endocrine organ” to all effects. As a response to exercise, it interfaces with the whole body through the secretion of myokines, soluble cytokines, or chemokines [4]. Specific myokines, such as irisin, interleukin 6 (IL-6), and insulin growth factor 1 (IGF-1) not only drive autocrine anabolism in muscles, but also mediate anti-inflammatory response and bone and adipose tissue crosstalk via receptor-mediated paracrine/endocrine action [5,6][5][6]. In primary myocytes, more than hundreds of myokines have been characterized in humans and rodents although their biological function has been described for only 5% of these [4,7][4][7].
Remarkably, joints and bones are crucial organs among those with which the skeletal muscle interacts. In addition, their strict connection is not only necessary for movements but is of utmost importance for influencing their reciprocal metabolism, which is deeply mediated by mutual biochemical and molecular mechanisms [8]. The bone cell-derived proteins named osteokines (such as fibroblast growth factors, osteocalcin, nuclear factor kappa B receptor activator ligand (RANKL), IGF-1, or small molecule-like prostaglandin E2) influence the bone and muscle homeostasis directly or indirectly [9,10][9][10]. The bidirectional changes occurring between these tissues, which often extend to the adipose depots, are maintained by common endocrine soluble factors, as recently reviewed by Kirk et al., 2020 [11]. Moreover, to connect muscles to other tissues, such as bone, myotubes produce extracellular vesicles called exosomes in the extracellular medium in vitro or in body fluids and serum [12,13][12][13]. In fact, exosomes, budded from the sarcoplasmic membrane or from late endosome-multivesicular bodies, may transfer a multitude of mediators as myokines, muscle-specific mRNAs, and lipids crucial for muscle function and regeneration [14,15,16][14][15][16].
In vertebrate, the healthy skeletal muscles own a complex architecture that comprehends different cell types, including polynucleated myofibers, quiescent satellite cells, fibroblasts, adipocytes, and macrophages. Several myofibers group together in larger units, called fascicles, which are further associated with the total muscle [17]. Moreover, muscles are enveloped by intramuscular connective sheets, surrounded by the extracellular matrix, which is the site that hosts blood supply and innervation [18,19][18][19]. This highly differentiated system is based on a functional unit named sarcomere, which is the site of force generation characterized by actin and myosin filaments cross-linked with other structural proteins able to fix calcium ions [20]. Moreover, at subcellular level, adult myotubes contain a set of interrelated organelle-like mitochondria, sarcoplasmic reticulum, and lysosomes, which collaborate to produce energy, drive calcium flux, and dismantle dysfunctional proteins and cellular debris.
The presence of different myosin heavy chain (MYH) isoforms in myofibers permits the identification of different muscles in mouse and humans [21]. In rodents, muscles are classified according to four types of fibers: Slow type 1 or fast types 2A, 2X, and 2B. Conversely, human muscles contain three types of fibers: Slow type 1 and fast types 2A and 2X. Currently, in addition to a consolidated older classification, single fiber proteome and single nucleus transcriptome analysis characterize sarcoplasmic proteins and mitochondria for each fiber and measure oxidative metabolism and regeneration [22]. Type 2A and type 2X fibers, based on oxidative metabolism, contained the major number of mitochondria, while the fast highly glycolytic type 2B fiber contains the lower number [23].
Mitochondria are scattered in sarcomere I band within glycolytic fibers, while in aerobic fast fibers they accumulated in both I and A bands [24]. However, a mixture of different myofibers in human skeletal muscles characterizes the adaptability of fast-twitch type 2 fibers, and the abundance of dystrophin and integrin in the myotendinous junction in type 2X fibers [25].
During aging, skeletal muscles face a multitude of structural and functional changes which progressively determine a loss in mass and strength. The cellular alteration is one of the main consequences in terms of the number of muscle fibers and their cross-sectional area [26]. Since satellite cells, the cells appointed to self-renew, are reduced in number, adipocytes and the fibrous connective tissue replace myofibers, while the paucity of elastic fibers affect adaptability [27,28][27][28]. Quiescent satellite cells rely on glycolytic metabolism; however, in response to injury or excessive loading, they use an oxidative metabolism even if their regenerative potential and number dramatically decrease in aging [29]. Remarkably, altered mitochondrial biogenesis in aged muscle leads to altered muscle repair [30]. At an early stage of aging, muscle composition changes, and type 2 fibers dramatically decrease in mice [31].
Abnormal extracellular matrix expansion and collagen I infiltration impair motility and regeneration [32]. In addition, scarce blood supply and degenerated neuromuscular junction characterized aged muscles, contributing to weakness and immobility [33]. Intramuscular adipose tissue increases in advancing age, along with resident macrophages, mainly type M2 in mice and human muscles [34]. However, low chronic grade of systemic inflammation affects muscle performance and is implicated in aging sarcopenia [35]. All of the above-mentioned changes contribute to the determination of the structural and functional deterioration occurring in skeletal muscle during aging, leading progressively to the resulting phenotype characterizing sarcopenia, and thus to the decrease in mobility, the loss of independence, and the increase in the risk of other morbidities in bones and joints [26]. Similar to skeletal muscle, the human skeleton experiences changes during life and aging. Indeed, although bone is the hardest tissue in the body, it undergoes complete remodeling during the lifespan, approximately every 10 years [36]. Long bones, the fundamental components of mobile synovial joints, consist of highly specialized trabeculae surrounding the bone marrow cavity, enveloped by a connective layer rich in vessels and nerves. Constant changes in thickness and mineral density in bones are the result of the remodeling process, which is the balance between osteoblasts (bone formation), osteoclasts (bone resorption), and their transition to quiescent osteocytes [37]. These last cells, estimated to be 42 billion in human skeleton, represent a crucial source of multiple endocrine signals, mainly cytokine receptor activator of RANKL driving osteoclast formation [38,39][38][39]. In postmenopausal women, the progression of life span and reduced estrogenic signaling cause the loss of trabecular bone thickness and mineral density and is predisposed to fractures and hospitalization [40]. Osteoclast overactivation triggers osteoporosis, and degenerative inflammation in articular cartilage is predisposed to disease-like osteoarthritis and autoimmune rheumatic arthritis in aging sarcopenia [41].
Since muscle and bone share genetic, lifestyle, and hormonal determinants, the multifactorial and complex pathophysiology and etiology of osteoporosis and sarcopenia have a synchronic relationship [42]. Recent studies highlighted a correlation between body composition, muscle strength, and bone mineral density [43]. Particularly, He et al. (2016) found that osteoporosis and sarcopenia are frequently concomitant in older women, supporting the growing evidence, not without caution, that healthy bone is progressively impaired with advancing sarcopenia stages [44]. Specifically, muscle and bone mass can be modulated by multiple factors, their dysfunctional alterations due to common environmental stimuli often co-exist, and the clinical consequences surpass the musculoskeletal system [6], as we will see in the next paragraphs[6].
Highly differentiated biological systems, such as skeletal muscles and bones depend on a biological environment where protein anabolism and catabolism are balanced.
In both systems, metabolic homeostasis is maintained by autophagy, a crucial housekeeping “recycling” process able to dismantle dysfunctional macromolecules and organelles [45].
Moreover, the quality control of mitochondria and other damaged macromolecules is one of the essential mechanisms for maintaining the cellular homeostasis [46]; therefore, this applies to muscle cells. In fact, the selective autophagy occurs to specifically remove damaged and dysfunctional organelles whose excessive rates are hallmark of sarcopenia and correlated musculoskeletal diseases, including bone metabolic disorders [47,48][47][48]. This is a crucial point since an appropriate induction and normal regulation of autophagy by genetic, nutritional, and pharmacological treatments can alleviate age-related diseases, and thus extend longevity [49].
Currently, there is no effective pharmacological therapy to alleviate sarcopenia [50], whereas the long-time treatment of age-associated bone metabolic disorders, osteoarthritis, and rheumatoid arthritis based on corticosteroids is associated with negative side effects [51]. In addition, bisphosphonates are not resolutive for bone mineral density in osteoporosis [52]. On the one hand, pharmacological treatments can have negative effects in addition to a proper autophagy regulation. On the other hand, some natural compounds found in health-related foods can instead safely induce appropriate autophagy. Among these natural compounds, polyamines represent autophagy-stimulating molecules that have attracted great attention in the last decade. Another interesting and safe modulator that was recently identified as an autophagy inducer in vivo is physical exercise [53,54,55,56,57,58,59][53][54][55][56][57][58][59]. Indeed, proper tuning of autophagy and mitophagy extent by selected “modulators”, such as safe nutraceuticals, for instance, polyamines and physical exercise, are an attractive emerging objective to limit aging-induced muscle atrophy [60,61], which is the major focus of the present narrative review[60][61].

2. A Potential Therapeutic Target in Aging and Related Pathologies

Dysregulation of polyamines and their metabolic enzymes have been associated with several pathologies [149][62]. Many studies documented a relationship between polyamine levels, drug response, apoptosis, and the etiology of adverse pathological conditions, including cancer [140][63]. Sanchez-Jimenez et al. (2019) showed that altered polyamine metabolism was related to neurodegenerative diseases, mental retardation, psychiatric disorders, and inflammation [150][64]. In detail, in neurological functions, polyamines should play a role as neurotransmitters or modulators of neurotransmission. The effects of polyamine on trained learning and memory, and the neuroprotective rules of spermidine supplementation have been recently reviewed [139,150,151][64][65][66]. Moreover, a loss of polyamine homeostasis seems to be associated with psychiatric disorders, such as depression [152][67], anxiety [153][68], schizophrenia, and epilepsy [154][69]. Regarding the immune responses, polyamine could act as immunostimulatory in immune cell differentiation, activation, recruitment, and as modulator of the inflammatory reaction [139,150,151,155][64][65][66][70]. Furthermore, polyamines are essential for the treatment of metabolic syndrome, obesity, and type 2 diabetes [139][65]. In addition, polyamine levels decrease with age in many organisms, as well as in humans [156,157,158][71][72][73]. In fact, the levels of the two main studied polyamines, spermine and spermidine, were significantly altered in skeletal muscles of aged mice [159][74]. Remarkably, spermine and spermidine are natural autophagy-inducers [156][71] and have anti-aging effects. A study showed that 2 weeks of spermidine administration in elderly mice reversed the age-associated defect in autophagy and mitophagy in muscle stem cell, and enhanced muscle regeneration [121,160][75][76]. The suppression of stem cell senescence by spermidine is dependent on autophagy restoration in satellite cells since spermidine promotes mitochondrial function. These stemness-enhancing effects ensure muscle regeneration and reduction in myopathy [139][65]. Due to their effect on skeletal muscle atrophy and hypertrophy, the polyamines’ role in skeletal muscle disease, such as sarcopenia, is evident as reported in a recent review [144][77]. Furthermore, as a geroprotector, spermidine decreases markers of age-related oxidative damage in mice [156][71], preserves mitochondrial function, holds anti-inflammatory properties, and prevents stem cell senescence [161][78]. In particular, the anti-inflammatory properties are exerted by several mechanisms that directly result on the reduction in the expression of pro-inflammatory cytokines, as recently well-reviewed by Ni et al. [162][79]: (I) Inhibition of accumulation of ROS, (II) decrease in the expression levels of tumor necrosis factor-α (TNF-α), (III) suppression of the translocation in the nucleus of nuclear factor-kB (NF-kB) p65 subunit [163][80], (IV) inhibition of the expression of IL-18 and IL-1β [162[79][81],164], and (V) attenuation of receptor interacting protein (RIP1) deubiquitination in macrophages, chondrocytes, and synovial tissue of osteoarthritic mice model [165,166][82][83]. Moreover, their supplementation contrasts the age-associated disruption of circadian rhythm in mice [167][84]. In addition, increasing polyamine levels through dietary supplementation may contribute to longevity [144,156][71][77]. It has been demonstrated that polyamines reduce age-related damage in short-lived mice [168][85] and counteract cardiovascular disease, neurodegeneration, and cancer [139,145,154][65][69][86]. Based on this evidence, polyamine (as supplementation or nutritional intake) could represent a potential preventive agent in the fight against age-derived muscle disability. Nonetheless, as reported in a recent review, the effects of polyamines in human and animal health can be dualistic depending on the cellular health state [151][66], which can be beneficial in healthy cells by boosting physiological processes to reduce aging- and stress-induced responses or detrimental in unhealthy cells under pathological conditions, such as cancer and neurological disorders [140[63][87],169], as above-mentioned. In fact, the functions exploited by polyamines in the complex lead toward the control of cellular death and life [143][88]. Cell death regulation, autophagy regulation, cell differentiation and reprogramming, and protein synthesis are all effects that might induce or modulate polyamines and trigger cellular changes for the promotion of both their growth and death via different mechanisms. Moreover, reversed reactions can be induced in cytoplasm and nucleus, making the understanding of the interaction of polyamines with aging, stress, and disorders even more complex to understand [169][87]. Although it seems that polyamines, in particular, spermidine have beneficial effects in promoting longevity in healthy organisms [156][71], wresearche rs are still far away from comprehending their potential in age-related diseases, which remains putative in humans since this has only been investigated in non-human models to date. Finally, spermidine received great attention for its potential to target some mechanisms behind autophagy induction, whose role might be a good target for increasing longevity and perhaps to prevent some diseases based on the exacerbation of the aging process, for example, sarcopenia in aged muscle.

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