Polyamines and Physical Activity in Musculoskeletal Diseases: Comparison
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.

References

  1. Argilés, J.M.; Campos, N.; Lopez-Pedrosa, J.M.; Rueda, R.; Rodriguez-Mañas, L. Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease. J. Am. Med. Dir. Assoc. 2016, 17, 789–796.
  2. Periasamy, M.; Herrera, J.L.; Reis, F.C.G. Skeletal Muscle Thermogenesis and Its Role in Whole Body Energy Metabolism. Diabetes Metab. J. 2017, 41, 327.
  3. Bian, A.; Ma, Y.; Zhou, X.; Guo, Y.; Wang, W.; Zhang, Y.; Wang, X. Association between Sarcopenia and Levels of Growth Hormone and Insulin-like Growth Factor-1 in the Elderly. BMC Musculoskelet. Disord. 2020, 21, 214.
  4. Severinsen, M.C.K.; Pedersen, B.K. Muscle–Organ Crosstalk: The Emerging Roles of Myokines. Endocr. Rev. 2020, 41, 594–609.
  5. Chen, W.; Wang, L.; You, W.; Shan, T. Myokines Mediate the Cross Talk between Skeletal Muscle and Other Organs. J. Cell. Physiol. 2021, 236, 2393–2412.
  6. Bosco, F.; Musolino, V.; Gliozzi, M.; Nucera, S.; Carresi, C.; Zito, M.C.; Scarano, F.; Scicchitano, M.; Reale, F.; Ruga, S.; et al. The Muscle to Bone Axis (and Viceversa): An Encrypted Language Affecting Tissues and Organs and yet to Be Codified? Pharmacol. Res. 2021, 165, 105427.
  7. Febbraio, M.A.; Pedersen, B.K. Who Would Have Thought—Myokines Two Decades On. Nat. Rev. Endocrinol. 2020, 16, 619–620.
  8. Lara-Castillo, N.; Johnson, M.L. Bone-Muscle Mutual Interactions. Curr. Osteoporos. Rep. 2020, 18, 408–421.
  9. Ono, T.; Hayashi, M.; Sasaki, F.; Nakashima, T. RANKL Biology: Bone Metabolism, the Immune System, and Beyond. Inflamm. Regen. 2020, 40, 2.
  10. Tresguerres, F.G.F.; Torres, J.; López-Quiles, J.; Hernández, G.; Vega, J.A.; Tresguerres, I.F. The Osteocyte: A Multifunctional Cell within the Bone. Ann. Anat.-Anat. Anz. 2020, 227, 151422.
  11. Kirk, B.; Feehan, J.; Lombardi, G.; Duque, G. Muscle, Bone, and Fat Crosstalk: The Biological Role of Myokines, Osteokines, and Adipokines. Curr. Osteoporos. Rep. 2020, 18, 388–400.
  12. Rome, S.; Forterre, A.; Mizgier, M.L.; Bouzakri, K. Skeletal Muscle-Released Extracellular Vesicles: State of the Art. Front. Physiol. 2019, 10, 929.
  13. Herrmann, M.; Engelke, K.; Ebert, R.; Müller-Deubert, S.; Rudert, M.; Ziouti, F.; Jundt, F.; Felsenberg, D.; Jakob, F. Interactions between Muscle and Bone—Where Physics Meets Biology. Biomolecules 2020, 10, 432.
  14. Aoi, W.; Tanimura, Y. Roles of Skeletal Muscle-Derived Exosomes in Organ Metabolic and Immunological Communication. Front. Endocrinol. 2021, 12, 697204.
  15. Mytidou, C.; Koutsoulidou, A.; Katsioloudi, A.; Prokopi, M.; Kapnisis, K.; Michailidou, K.; Anayiotos, A.; Phylactou, L.A. Muscle-derived Exosomes Encapsulate MyomiRs and Are Involved in Local Skeletal Muscle Tissue Communication. FASEB J. 2021, 35, e21279.
  16. Sahu, A.; Clemens, Z.J.; Shinde, S.N.; Sivakumar, S.; Pius, A.; Bhatia, A.; Picciolini, S.; Carlomagno, C.; Gualerzi, A.; Bedoni, M.; et al. Regulation of Aged Skeletal Muscle Regeneration by Circulating Extracellular Vesicles. Nat. Aging 2021, 1, 1148–1161.
  17. Kröger, S.; Watkins, B. Muscle Spindle Function in Healthy and Diseased Muscle. Skelet. Muscle 2021, 11, 3.
  18. Loreti, M.; Sacco, A. The Jam Session between Muscle Stem Cells and the Extracellular Matrix in the Tissue Microenvironment. NPJ Regen. Med. 2022, 7, 16.
  19. Csapo, R.; Gumpenberger, M.; Wessner, B. Skeletal Muscle Extracellular Matrix–What Do We Know About Its Composition, Regulation, and Physiological Roles? A Narrative Review. Front. Physiol. 2020, 11, 253.
  20. Wang, Z.; Grange, M.; Wagner, T.; Kho, A.L.; Gautel, M.; Raunser, S. The Molecular Basis for Sarcomere Organization in Vertebrate Skeletal Muscle. Cell 2021, 184, 2135–2150.e13.
  21. Schiaffino, S.; Reggiani, C. Fiber Types in Mammalian Skeletal Muscles. Physiol. Rev. 2011, 91, 1447–1531.
  22. Kim, M.; Franke, V.; Brandt, B.; Lowenstein, E.D.; Schöwel, V.; Spuler, S.; Akalin, A.; Birchmeier, C. Single-Nucleus Transcriptomics Reveals Functional Compartmentalization in Syncytial Skeletal Muscle Cells. Nat. Commun. 2020, 11, 6375.
  23. Schiaffino, S.; Reggiani, C.; Murgia, M. Fiber Type Diversity in Skeletal Muscle Explored by Mass Spectrometry-Based Single Fiber Proteomics. Histol. Histopathol. 2020, 35, 239–246.
  24. Bourdeau Julien, I.; Sephton, C.F.; Dutchak, P.A. Metabolic Networks Influencing Skeletal Muscle Fiber Composition. Front. Cell Dev. Biol. 2018, 6, 125.
  25. Murgia, M.; Nogara, L.; Baraldo, M.; Reggiani, C.; Mann, M.; Schiaffino, S. Protein Profile of Fiber Types in Human Skeletal Muscle: A Single-Fiber Proteomics Study. Skelet. Muscle 2021, 11, 24.
  26. McCormick, R.; Vasilaki, A. Age-Related Changes in Skeletal Muscle: Changes to Life-Style as a Therapy. Biogerontology 2018, 19, 519–536.
  27. Sousa-Victor, P.; García-Prat, L.; Muñoz-Cánoves, P. Control of Satellite Cell Function in Muscle Regeneration and Its Disruption in Ageing. Nat. Rev. Mol. Cell Biol. 2022, 23, 204–226.
  28. Fede, C.; Fan, C.; Pirri, C.; Petrelli, L.; Biz, C.; Porzionato, A.; Macchi, V.; De Caro, R.; Stecco, C. The Effects of Aging on the Intramuscular Connective Tissue. Int. J. Mol. Sci. 2022, 23, 11061.
  29. Chen, W.; Datzkiw, D.; Rudnicki, M.A. Satellite Cells in Ageing: Use It or Lose It. Open Biol. 2020, 10, 200048.
  30. Bellanti, F.; Lo Buglio, A.; Vendemiale, G. Muscle Delivery of Mitochondria-Targeted Drugs for the Treatment of Sarcopenia: Rationale and Perspectives. Pharmaceutics 2022, 14, 2588.
  31. Sayed, R.K.A.; de Leonardis, E.C.; Guerrero-Martínez, J.A.; Rahim, I.; Mokhtar, D.M.; Saleh, A.M.; Abdalla, K.E.H.; Pozo, M.J.; Escames, G.; López, L.C.; et al. Identification of Morphological Markers of Sarcopenia at Early Stage of Aging in Skeletal Muscle of Mice. Exp. Gerontol. 2016, 83, 22–30.
  32. Mahdy, M.A.A. Skeletal Muscle Fibrosis: An Overview. Cell Tissue Res. 2019, 375, 575–588.
  33. Zullo, A.; Fleckenstein, J.; Schleip, R.; Hoppe, K.; Wearing, S.; Klingler, W. Structural and Functional Changes in the Coupling of Fascial Tissue, Skeletal Muscle, and Nerves During Aging. Front. Physiol. 2020, 11, 592.
  34. Cui, C.-Y.; Ferrucci, L. Macrophages in Skeletal Muscle Aging. Aging 2020, 12, 3–4.
  35. Antuña, E.; Cachán-Vega, C.; Bermejo-Millo, J.C.; Potes, Y.; Caballero, B.; Vega-Naredo, I.; Coto-Montes, A.; Garcia-Gonzalez, C. Inflammaging: Implications in Sarcopenia. Int. J. Mol. Sci. 2022, 23, 15039.
  36. Kular, J.; Tickner, J.; Chim, S.M.; Xu, J. An Overview of the Regulation of Bone Remodelling at the Cellular Level. Clin. Biochem. 2012, 45, 863–873.
  37. Dallas, S.L.; Bonewald, L.F. Dynamics of the Transition from Osteoblast to Osteocyte. Ann. N. Y. Acad. Sci. 2010, 1192, 437–443.
  38. Xiong, J.; Piemontese, M.; Onal, M.; Campbell, J.; Goellner, J.J.; Dusevich, V.; Bonewald, L.; Manolagas, S.C.; O’Brien, C.A. Osteocytes, Not Osteoblasts or Lining Cells, Are the Main Source of the RANKL Required for Osteoclast Formation in Remodeling Bone. PLoS ONE 2015, 10, e0138189.
  39. Ikebuchi, Y.; Aoki, S.; Honma, M.; Hayashi, M.; Sugamori, Y.; Khan, M.; Kariya, Y.; Kato, G.; Tabata, Y.; Penninger, J.M.; et al. Coupling of Bone Resorption and Formation by RANKL Reverse Signalling. Nature 2018, 561, 195–200.
  40. Johnston, C.B.; Dagar, M. Osteoporosis in Older Adults. Med. Clin. N. Am. 2020, 104, 873–884.
  41. Laurent, M.R.; Dedeyne, L.; Dupont, J.; Mellaerts, B.; Dejaeger, M.; Gielen, E. Age-Related Bone Loss and Sarcopenia in Men. Maturitas 2019, 122, 51–56.
  42. Verschueren, S.; Gielen, E.; O’Neill, T.W.; Pye, S.R.; Adams, J.E.; Ward, K.A.; Wu, F.C.; Szulc, P.; Laurent, M.; Claessens, F.; et al. Sarcopenia and Its Relationship with Bone Mineral Density in Middle-Aged and Elderly European Men. Osteoporos. Int. 2013, 24, 87–98.
  43. Lima, R.M.; de Oliveira, R.J.; Raposo, R.; Neri, S.G.R.; Gadelha, A.B. Stages of Sarcopenia, Bone Mineral Density, and the Prevalence of Osteoporosis in Older Women. Arch. Osteoporos. 2019, 14, 38.
  44. He, H.; Liu, Y.; Tian, Q.; Papasian, C.J.; Hu, T.; Deng, H.-W. Relationship of Sarcopenia and Body Composition with Osteoporosis. Osteoporos. Int. 2016, 27, 473–482.
  45. Pohl, C.; Dikic, I. Cellular Quality Control by the Ubiquitin-Proteasome System and Autophagy. Science 2019, 366, 818–822.
  46. Langeh, U.; Kumar, V.; Kumar, A.; Kumar, P.; Singh, C.; Singh, A. Cellular and Mitochondrial Quality Control Mechanisms in Maintaining Homeostasis in Aging. Rejuvenation Res. 2022, 25, 208–222.
  47. Wang, S.; Deng, Z.; Ma, Y.; Jin, J.; Qi, F.; Li, S.; Liu, C.; Lyu, F.-J.; Zheng, Q. The Role of Autophagy and Mitophagy in Bone Metabolic Disorders. Int. J. Biol. Sci. 2020, 16, 2675–2691.
  48. Coen, P.M.; Musci, R.V.; Hinkley, J.M.; Miller, B.F. Mitochondria as a Target for Mitigating Sarcopenia. Front. Physiol. 2019, 9, 1883.
  49. Madeo, F.; Tavernarakis, N.; Kroemer, G. Can Autophagy Promote Longevity? Nat. Cell Biol. 2010, 12, 842–846.
  50. Lo, J.H.-T.; Yiu, T.; Ong, M.T.-Y.; Lee, W.Y.-W. Sarcopenia: Current Treatments and New Regenerative Therapeutic Approaches. J. Orthop. Translat. 2020, 23, 38–52.
  51. Fassio, A.; Idolazzi, L.; Jaber, M.A.; Dartizio, C.; Viapiana, O.; Rossini, M.; Gatti, D. The Negative Bone Effects of the Disease and of Chronic Corticosteroid Treatment in Premenopausal Women Affected by Rheumatoid Arthritis. Reumatismo 2016, 68, 65–71.
  52. Nagase, Y.; Nagashima, M.; Shimane, K.; Nishikawa, T.; Naito, M.; Tanaka, S. Effect of TNF Inhibitors with Bisphosphonates vs Bisphosphonates Alone on Bone Mineral Density and Bone and Cartilage Biomarkers at 1 Year in Patients with Rheumatoid Arthritis: A Prospective Study. Mod. Rheumatol. 2022, 32, 517–521.
  53. Halling, J.F.; Ringholm, S.; Olesen, J.; Prats, C.; Pilegaard, H. Exercise Training Protects against Aging-Induced Mitochondrial Fragmentation in Mouse Skeletal Muscle in a PGC-1α Dependent Manner. Exp. Gerontol. 2017, 96, 1–6.
  54. Laker, R.C.; Drake, J.C.; Wilson, R.J.; Lira, V.A.; Lewellen, B.M.; Ryall, K.A.; Fisher, C.C.; Zhang, M.; Saucerman, J.J.; Goodyear, L.J.; et al. Ampk Phosphorylation of Ulk1 Is Required for Targeting of Mitochondria to Lysosomes in Exercise-Induced Mitophagy. Nat. Commun. 2017, 8, 548.
  55. Lenhare, L.; Crisol, B.M.; Silva, V.R.R.; Katashima, C.K.; Cordeiro, A.V.; Pereira, K.D.; Luchessi, A.D.; da Silva, A.S.R.; Cintra, D.E.; Moura, L.P.; et al. Physical Exercise Increases Sestrin 2 Protein Levels and Induces Autophagy in the Skeletal Muscle of Old Mice. Exp. Gerontol. 2017, 97, 17–21.
  56. Erlich, A.T.; Brownlee, D.M.; Beyfuss, K.; Hood, D.A. Exercise Induces TFEB Expression and Activity in Skeletal Muscle in a Pgc-1α-Dependent Manner. Am. J. Physiol. Cell Physiol. 2018, 314, C62–C72.
  57. Li, F.-H.; Li, T.; Ai, J.-Y.; Sun, L.; Min, Z.; Duan, R.; Zhu, L.; Liu, Y.; Liu, T.C.-Y. Beneficial Autophagic Activities, Mitochondrial Function, and Metabolic Phenotype Adaptations Promoted by High-Intensity Interval Training in a Rat Model. Front. Physiol. 2018, 9, 571.
  58. Zeng, Z.; Liang, J.; Wu, L.; Zhang, H.; Lv, J.; Chen, N. Exercise-Induced Autophagy Suppresses Sarcopenia Through Akt/MTOR and Akt/FoxO3a Signal Pathways and AMPK-Mediated Mitochondrial Quality Control. Front. Physiol. 2020, 11, 583478.
  59. Wang, P.; Li, C.G.; Zhou, X.; Cui, D.; Ouyang, T.; Chen, W.; Ding, S. A Single Bout of Exhaustive Treadmill Exercise Increased AMPK Activation Associated with Enhanced Autophagy in Mice Skeletal Muscle. Clin. Exp. Pharmacol. Physiol. 2022, 49, 536–543.
  60. Mito, T.; Vincent, A.E.; Faitg, J.; Taylor, R.W.; Khan, N.A.; McWilliams, T.G.; Suomalainen, A. Mosaic Dysfunction of Mitophagy in Mitochondrial Muscle Disease. Cell Metab. 2022, 34, 197–208.e5.
  61. Doblado, L.; Lueck, C.; Rey, C.; Samhan-Arias, A.K.; Prieto, I.; Stacchiotti, A.; Monsalve, M. Mitophagy in Human Diseases. Int. J. Mol. Sci. 2021, 22, 3903.
  62. Cervelli, M.; Averna, M.; Vergani, L.; Pedrazzi, M.; Amato, S.; Fiorucci, C.; Rossi, M.N.; Maura, G.; Mariottini, P.; Cervetto, C.; et al. The Involvement of Polyamines Catabolism in the Crosstalk between Neurons and Astrocytes in Neurodegeneration. Biomedicines 2022, 10, 1756.
  63. Pegg, A.E. Functions of Polyamines in Mammals. J. Biol. Chem. 2016, 291, 14904–14912.
  64. Sánchez-Jiménez, F.; Medina, M.Á.; Villalobos-Rueda, L.; Urdiales, J.L. Polyamines in Mammalian Pathophysiology. Cell. Mol. Life Sci. 2019, 76, 3987–4008.
  65. Madeo, F.; Eisenberg, T.; Pietrocola, F.; Kroemer, G. Spermidine in Health and Disease. Science 2018, 359, aan2788.
  66. Handa, A.K.; Fatima, T.; Mattoo, A.K. Polyamines: Bio-Molecules with Diverse Functions in Plant and Human Health and Disease. Front. Chem. 2018, 6, 10.
  67. Zhu, H.-J.; Appel, D.I.; Gründemann, D.; Richelson, E.; Markowitz, J.S. Evaluation of Organic Cation Transporter 3 (SLC22A3) Inhibition as a Potential Mechanism of Antidepressant Action. Pharmacol. Res. 2012, 65, 491–496.
  68. Le Roy, C.; Laboureyras, E.; Laulin, J.-P.; Simonnet, G. A Polyamine-Deficient Diet Opposes Hyperalgesia, Tolerance and the Increased Anxiety-like Behaviour Associated with Heroin Withdrawal in Rats. Pharmacol. Biochem. Behav. 2013, 103, 510–519.
  69. Baroli, G.; Sanchez, J.; Agostinelli, E.; Mariottini, P.; Cervelli, M. Polyamines: The Possible Missing Link between Mental Disorders and Epilepsy (Review). Int. J. Mol. Med. 2019, 45, 3–9.
  70. Bae, D.-H.; Lane, D.J.R.; Jansson, P.J.; Richardson, D.R. The Old and New Biochemistry of Polyamines. Biochim. Biophys. Acta (BBA)-Gen. Subj. 2018, 1862, 2053–2068.
  71. Eisenberg, T.; Knauer, H.; Schauer, A.; Büttner, S.; Ruckenstuhl, C.; Carmona-Gutierrez, D.; Ring, J.; Schroeder, S.; Magnes, C.; Antonacci, L.; et al. Induction of Autophagy by Spermidine Promotes Longevity. Nat. Cell Biol. 2009, 11, 1305–1314.
  72. Pucciarelli, S.; Moreschini, B.; Micozzi, D.; De Fronzo, G.S.; Carpi, F.M.; Polzonetti, V.; Vincenzetti, S.; Mignini, F.; Napolioni, V. Spermidine and Spermine Are Enriched in Whole Blood of Nona/Centenarians. Rejuvenation Res. 2012, 15, 590–595.
  73. Gupta, V.K.; Scheunemann, L.; Eisenberg, T.; Mertel, S.; Bhukel, A.; Koemans, T.S.; Kramer, J.M.; Liu, K.S.Y.; Schroeder, S.; Stunnenberg, H.G.; et al. Restoring Polyamines Protects from Age-Induced Memory Impairment in an Autophagy-Dependent Manner. Nat. Neurosci. 2013, 16, 1453–1460.
  74. Uchitomi, R.; Hatazawa, Y.; Senoo, N.; Yoshioka, K.; Fujita, M.; Shimizu, T.; Miura, S.; Ono, Y.; Kamei, Y. Metabolomic Analysis of Skeletal Muscle in Aged Mice. Sci. Rep. 2019, 9, 10425.
  75. García-Prat, L.; Martínez-Vicente, M.; Perdiguero, E.; Ortet, L.; Rodríguez-Ubreva, J.; Rebollo, E.; Ruiz-Bonilla, V.; Gutarra, S.; Ballestar, E.; Serrano, A.L.; et al. Autophagy Maintains Stemness by Preventing Senescence. Nature 2016, 529, 37–42.
  76. Zhang, L.; Gong, H.; Sun, Q.; Zhao, R.; Jia, Y. Spermidine-Activated Satellite Cells Are Associated with Hypoacetylation in ACVR2B and Smad3 Binding to Myogenic Genes in Mice. J. Agric. Food Chem. 2018, 66, 540–550.
  77. Cervelli, M.; Leonetti, A.; Duranti, G.; Sabatini, S.; Ceci, R.; Mariottini, P. Skeletal Muscle Pathophysiology: The Emerging Role of Spermine Oxidase and Spermidine. Med. Sci. 2018, 6, 14.
  78. Madeo, F.; Carmona-Gutierrez, D.; Kepp, O.; Kroemer, G. Spermidine Delays Aging in Humans. Aging 2018, 10, 2209–2211.
  79. Ni, Y.-Q.; Liu, Y.-S. New Insights into the Roles and Mechanisms of Spermidine in Aging and Age-Related Diseases. Aging Dis. 2021, 12, 1948.
  80. Choi, Y.; Park, H. Anti-Inflammatory Effects of Spermidine in Lipopolysaccharide-Stimulated BV2 Microglial Cells. J. Biomed. Sci. 2012, 19, 31.
  81. Paul, S.; Kang, S.C. Natural Polyamine Inhibits Mouse Skin Inflammation and Macrophage Activation. Inflamm. Res. 2013, 62, 681–688.
  82. Jeong, J.-W.; Cha, H.-J.; Han, M.H.; Hwang, S.J.; Lee, D.-S.; Yoo, J.S.; Choi, I.-W.; Kim, S.; Kim, H.-S.; Kim, G.-Y.; et al. Spermidine Protects against Oxidative Stress in Inflammation Models Using Macrophages and Zebrafish. Biomol. Ther. 2018, 26, 146–156.
  83. Chen, Z.; Lin, C.-X.; Song, B.; Li, C.-C.; Qiu, J.-X.; Li, S.-X.; Lin, S.-P.; Luo, W.-Q.; Fu, Y.; Fang, G.-B.; et al. Spermidine Activates RIP1 Deubiquitination to Inhibit TNF-α-Induced NF-ΚB/P65 Signaling Pathway in Osteoarthritis. Cell Death Dis. 2020, 11, 503.
  84. Zwighaft, Z.; Aviram, R.; Shalev, M.; Rousso-Noori, L.; Kraut-Cohen, J.; Golik, M.; Brandis, A.; Reinke, H.; Aharoni, A.; Kahana, C.; et al. Circadian Clock Control by Polyamine Levels through a Mechanism That Declines with Age. Cell Metab. 2015, 22, 874–885.
  85. Soda, K.; Dobashi, Y.; Kano, Y.; Tsujinaka, S.; Konishi, F. Polyamine-Rich Food Decreases Age-Associated Pathology and Mortality in Aged Mice. Exp. Gerontol. 2009, 44, 727–732.
  86. Ceci, R.; Duranti, G.; Leonetti, A.; Pietropaoli, S.; Spinozzi, F.; Marcocci, L.; Amendola, R.; Cecconi, F.; Sabatini, S.; Mariottini, P.; et al. Adaptive Responses of Heart and Skeletal Muscle to Spermine Oxidase Overexpression: Evaluation of a New Transgenic Mouse Model. Free Radic. Biol. Med. 2017, 103, 216–225.
  87. Sagar, N.A.; Tarafdar, S.; Agarwal, S.; Tarafdar, A.; Sharma, S. Polyamines: Functions, Metabolism, and Role in Human Disease Management. Med. Sci. 2021, 9, 44.
  88. Minois, N.; Carmona-Gutierrez, D.; Madeo, F. Polyamines in Aging and Disease. Aging 2011, 3, 716–732.
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