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Review

Muscle Delivery of Mitochondria-Targeted Drugs for the Treatment of Sarcopenia: Rationale and Perspectives

Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
*
Author to whom correspondence should be addressed.
Pharmaceutics 2022, 14(12), 2588; https://doi.org/10.3390/pharmaceutics14122588
Submission received: 31 October 2022 / Revised: 18 November 2022 / Accepted: 19 November 2022 / Published: 24 November 2022
(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

Abstract

:
An impairment in mitochondrial homeostasis plays a crucial role in the process of aging and contributes to the incidence of age-related diseases, including sarcopenia, which is defined as an age-dependent loss of muscle mass and strength. Mitochondrial dysfunction exerts a negative impact on several cellular activities, including bioenergetics, metabolism, and apoptosis. In sarcopenia, mitochondria homeostasis is disrupted because of reduced oxidative phosphorylation and ATP generation, the enhanced production of reactive species, and impaired antioxidant defense. This review re-establishes the most recent evidence on mitochondrial defects that are thought to be relevant in the pathogenesis of sarcopenia and that may represent promising therapeutic targets for its prevention/treatment. Furthermore, we describe mechanisms of action and translational potential of promising mitochondria-targeted drug delivery systems, including molecules able to boost the metabolism and bioenergetics, counteract apoptosis, antioxidants to scavenge reactive species and decrease oxidative stress, and target mitophagy. Even though these mitochondria-delivered strategies demonstrate to be promising in preclinical models, their use needs to be promoted for clinical studies. Therefore, there is a compelling demand to further understand the mechanisms modulating mitochondrial homeostasis, to characterize powerful compounds that target muscle mitochondria to prevent sarcopenia in aged people.

1. Introduction

In recent years, life expectancy has enormously increased all over the world. This has been accompanied by growing health problems related to aging, since the extension of the expected lifespan is unavoidably followed by biological modifications that affect the human body. In particular, age-dependent changes related to muscle mass and function are notably evident as individuals become older and older. The loss of muscle mass during ageing, followed by a decline in physical function and mobility, is defined by the term ”sarcopenia” [1]. According to a recently revised European consensus, sarcopenia is typically characterized by low muscle strength, quantity, and quality [2].
The pathogenesis of sarcopenia is extremely complicated and multifactorial, so the therapeutic approach needs to be multimodal [3]. Even though several age-related diseases (including diabetes mellitus, osteoporosis, neurodegenerative, cardiovascular, and respiratory disorders) facilitate sarcopenia, the homeostasis of muscle mass and strength is maintained through several hormonal and nutritional factors, as well as physical activity levels [4,5,6]. Indeed, sarcopenia develops as the result of a reduced protein intake, associated with failing anabolic pathways modulated by the growth hormone (GH)/insulin-like growth factor (IGF) and vitamin D, and chronic low-grade inflammation [7]. All these findings are related to the impairment of muscle bioenergetics, which mainly rely on mitochondrial metabolism and homeostasis [8]. Most research suggests that modifications in mitochondrial biogenesis, morphology, function, and dynamics may represent the key process in disrupted muscle function and quality [9].
Progression in mitochondrial research and biomedical technology encourages the development of drugs specifically targeted to mitochondria for therapeutic use [10]. Skeletal muscle is an attractive tissue for studying the concept of drug delivery, since it is easily accessible from the bloodstream and includes several specific receptors/transporters that can be used for the selective uptake of molecules [11]. After a description of the importance of mitochondria in the pathogenesis of sarcopenia, this review focuses on mitochondrial drug-delivery systems and muscle-targeted molecules. Considering that mitochondrial medicine is in its developmental stage, we aim to stimulate the progression of muscle mitochondria-directed therapeutics for the management of sarcopenia.

2. Age-Related Skeletal Muscle Changes and Sarcopenia

In humans, the reduction in skeletal muscle mass and function begins after the fourth decade [2]. Indeed, the aging process induces a loss of 30% in skeletal muscle mass, with a yearly rate of 0.64–0.70% in women and 0.80–0.98% in men [12,13]. The prevalence of sarcopenia may vary according to different definitions, settings, and sex. Recent meta-analyses reported a prevalence of 11% and 9% in community-dwelling men and women, respectively; the prevalence increased to 51% and 31% in nursing homes, and to 23% and 24% in hospitalized males and females, respectively [14,15].

2.1. Age-Related Modifications of Skeletal Muscle Metabolism and Proteostasis

In the human body, skeletal muscle represents the main metabolic tissue since it needs a considerable utilization of oxygen and macronutrients to generate ATP for contraction. In fact, during an intensive activity, skeletal muscle tissue takes account for 60% of the total body oxygen uptake. Furthermore, skeletal muscle regularly disposes of phosphocreatine and glycogen to guarantee partial energy in anaerobiosis [16].
The age-related decrease in skeletal muscle quality is linked to a reprogramming of tissue metabolism, which leads to an altered glucose, lipid, and protein uptake and consumption, with the consequent impairment of ATP production (Figure 1) [17].
The age-dependent disruption of the skeletal muscle metabolism is different between men and women since it is affected by sex hormones [18]. Indeed, changes in body composition characterized by skeletal muscle decline and visceral adipose tissue increase are greater in men, while women exhibit a lower capillarization of type II glycolytic myofibers [19].
Metabolism in old skeletal muscle is affected by the fiber composition, since type I slow-twitch fibers prefer to oxidize fatty acids, while the anaerobic glucose metabolism is favored by type II fast-twitch fibers. The loss of type II fibers is more consistent than type I fiber decline, exerting an impact on tissue metabolism [20]. Furthermore, a reduction in capillarization occurs in aged skeletal muscle, with a consequently reduced nutrient delivery [21,22].
In skeletal muscles enriched with type II fibers, there is a close link between the capillary-to-fiber ratio and muscle fiber size, so these muscles are particularly susceptible to age-related disruption [23]. Enzymes accounting for glycogen metabolism and glycolysis, as well as GLUT4 protein (the muscle-specific transporter-mediating insulin-dependent glucose uptake), are downregulated in aging skeletal muscle [24,25]. Furthermore, several modifications of insulin signaling, which contribute to insulin resistance and an altered glucose metabolism, occur in aged skeletal muscle [26]. Skeletal muscle steatosis in aging mainly relies on changes in lipid uptake and oxidation. Indeed, triglyceride storage in skeletal muscle occurs as a result of an increased uptake and decreased oxidation of palmitate in aged rodents [27,28]. Moreover, changes in proteostasis, characterized by the imbalance between protein synthesis and breakdown, folding and trafficking, in support of excess catabolism that triggers a loss of skeletal muscle quantity and quality, occur in aging [29]. Nevertheless, protein turnover can be influenced by several factors, including nutritional status, physical activity, and insulin sensitivity [30,31,32]. Modifications coming from these factors may somewhat contribute to the ongoing age-dependent impairment of muscle quality [33]. Skeletal muscle from old subjects is no more responsive to the availability of amino acids, losing the capacity to trigger protein synthesis and counterbalance breakdown; this model is referred to as anabolic resistance [34]. The conglomeration of aggregated proteins is a typical feature of proteostasis disruption; this may be triggered by the aging-related rise in oxidative injury [35,36]. Furthermore, the loss of proteostasis is dependent on the alteration of the autophagy–lysosomal and the ubiquitin–proteasomal systems, the two most determinant pathways for protein degradation [37].

2.2. Age-Dependent Morphological and Functional Changes in Skeletal Muscle

Most investigations refer to the loss of skeletal muscle mass as the main trigger of sarcopenia (leading to a decrease in muscle strength and performance); nevertheless, modifications in strength and performance may precede the loss of mass in aged people [13].
According to the speed of shortening and myosin ATPase activity, muscle fibers can be classified as fast (type II, white morphology) and slow (type I, red morphology, dependent on high capillarization and the myoglobin content, which provide more oxidative capacity) [38]. The age-related loss of skeletal muscle mass is linked to a reduction in both the number and size of muscle fibers [39]. These changes depend on the age-induced loss of motor units (MUs), which are identified as the muscle fibers innervated by a single soma of an alpha motor neuron located in the ventral horn of the spinal cord. Indeed, the loss of a MU induces fiber denervation and skeletal muscle atrophy. This loss may be compensated with MU remodeling, defined by the reinnervation of denervated muscle fibers by nearby axons; nevertheless, this remodeling is flawed in sarcopenia [40].
Muscle fibers represent approximately 70% of skeletal muscle composition in adult men, but these are decreased to approximately 50% in the elderly, due to an increase in connective tissue (fibrosis) and lipids (steatosis) that accumulate within the muscle (intermuscular adipose tissue, IMAT) and below the fascia [39]. In particular, IMAT is an independent predictor of gait-speed reduction in aging, impairing both muscle strength and muscle metabolism [19,41]. Furthermore, skeletal muscle fibrosis is probably the cause of impaired tissue regeneration [42]. Indeed, fibrosis is the final consequence of several events, including tissue degeneration, recurrent microtrauma, inflammatory cell infiltration, and fibroblast proliferation [29]. Lastly, the size of skeletal muscle fibers tends to reduce with age; although this occurs mostly in type II fibers, a decrease in the diameter of type I fibers has also been reported [43,44].
Skeletal muscle strength and performance are not exclusively dependent on mass and fibers, sustaining the hypothesis that a decrease in skeletal muscle quality—more than quantity—occurs with age [45]. Skeletal muscle quality can be defined as strength (or power) per unit of muscle mass and relies both on the architecture and on the metabolism of skeletal muscle tissue [13,46].
Modifications in the skeletal muscle architecture include changes in fiber number, composition, and size. The main features of skeletal muscle architecture include the cross-sectional area (CSA), pennation angle (PA, measured as the length of the fascicle between the superficial and deep aponeurosis), and fascicle length (FL, measured as the angle between fascicle and deep aponeurosis). While muscle strength is influenced by PA, the muscle shortening velocity is affected by FL [47]. Aging determines a progressive reduction in CSA, PA, and FL [46,48]. This decrease exerts a negative effect on skeletal muscle power, which can be defined as the amount of force generated per unit of time. With respect to the reduction in skeletal muscle function in aging, an average power loss of 72% is more perceptible than the decline in strength in the elderly rather than adults, as the speed of skeletal muscle fiber shortening is reversed on myosin heavy-chain ATPase [49].

3. Mitochondrial Involvement in Sarcopenia

Aerobic capacity declines with age, together with changes in skeletal muscle energy metabolism [46]. Effective skeletal muscle bioenergetics rely on mitochondria, and mitochondrial dysfunction is one of the main hallmarks of aging [50]. Mitochondria in skeletal muscle are located below the sarcolemma (subsarcolemmal, SS) or between the myofibrils (intermyofibrillar, IMF); SS and IMF mitochondria are characterized by peculiar morphological and biochemical characteristics [51,52,53]. Age-related changes in skeletal muscle mitochondria involve the morphology, dynamics (fission and fusion), function (bioenergetics and apoptosis regulation), and turnover (biogenesis and mitophagy).

3.1. Age-Related Alterations in Morphology and Dynamics of Skeletal Muscle Mitochondria

Research on morphology in aged skeletal muscle describes giant mitochondria with disrupted cristae [54]. Furthermore, compared with the skeletal muscle of young/adults, old SS mitochondria seem fragmented and positioned in a thin layer, while IMF mitochondria appear less reticular [55]. Of interest, a decrease in IMF size was reported in old people, particularly in women more than men, although there were no differences in skeletal muscle size between both sexes [56]. Morphological alterations in old skeletal muscle mitochondria may result from changes in mitochondrial dynamics, characterized by an imbalance that enhances fission rather than fusion [57]. Mitochondrial dynamics can be dysregulated by mtDNA mutations, since old mice expressing a defective mtDNA polymerase gamma exhibited enhanced mitochondrial fission in skeletal muscle [58]. Nevertheless, a higher mitochondrial fusion was described in skeletal muscle from old versus young mice [59]. A change toward mitochondrial fusion rather than fission was further described in the skeletal muscle of old hip-fractured patients [60]. A knock-out of fusion-related proteins (mitofusins, Mfn1/2) in skeletal muscle caused higher mtDNA mutations and tissue atrophy [61]. However, skeletal muscle degeneration and atrophy were described as a result of the deletion of the fission-related protein Drp1 [62]. Taken together, these studies suggest that modifications of mitochondrial dynamics in skeletal muscle and their commitment in sarcopenia need to be clarified.

3.2. Mitochondrial Dysfunction and Apoptosis in Old Skeletal Muscle

Dysfunctional mitochondria cause both the exhaustion of ATP and excess of reactive species, with the consequent initiation of damaging cellular pathways. In old skeletal muscle, decreases in mitochondrial activity of the enzymes involved in the tricarboxylic acid cycle, oxygen consumption, and ATP synthesis are reported [63]. Moreover, mitochondrial dysfunction triggers apoptosis, with a negative impact on skeletal muscle quality [64].
Among the worsened mitochondrial functions in old skeletal muscle, the activity of metabolic enzymes (such as citrate synthase) and oxidative phosphorylation (OXPHOS) complexes, protein synthesis, and ATP production rate (mostly caused by an increase in mitochondrial uncoupling) were described [65,66,67,68,69]. However, it is worth noting that mitochondrial function in old skeletal muscle can be preserved with durable and intense physical activity [70,71,72]. To comply with this statement, exercise-mimicking compounds, such as AMP-activated protein kinase or peroxisome proliferator-activated receptor-δ (PPAR-δ) agonists, might act synergistically with mitochondria-targeted therapies to improve muscle quality [73].
Age-dependent reduction in mitochondrial gene expression is described when the transcriptome of old skeletal muscle is compared to young people, although proteomic investigations are controversial, suggesting the need for further studies [74]. Notably, genes related to mitochondrial structure and function are downregulated in old women compared to men, suggesting that females may be more prone to age-dependent mitochondrial impairment in skeletal muscle [75].
In sarcopenia, mtDNA and mitochondrial electron transport chain (ETC) changes are triggered by oxidative stress [76]. Indeed, the highest prevalence of mtDNA deletions is reported in those skeletal muscle fibers exposed to oxidative injury [77,78]. Increased mtDNA deletions are related to modifications of mitochondrial enzymes in old primates and humans [79,80]. An inactive lifestyle in old age is related to mitochondrial dysfunction and oxidative injury in human skeletal muscle, so physical activity may prevent mitochondrial-dependent sarcopenia [80,81]. Induced mtDNA mutations in the skeletal muscle of mice caused a disruption in ETC assembly and function, impairing mitochondrial bioenergetics and ATP homeostasis, and triggering apoptosis and sarcopenia [82]. Dysfunctional mitochondria were also reported in spinal motor neurons from old humans, contributing to the denervation and collapse of skeletal muscle quality [83]. Notably, the denervation of skeletal muscle fibers triggers mitochondrial reactive species even in nearby innervated fibers, indicating a collateral mechanism in sarcopenia [84].
Dysfunctional mitochondria may trigger apoptosis in old skeletal muscle. Indeed, mitochondria from aged skeletal muscle exhibit a high production rate of reactive species and low calcium internalization, with the consequent opening of the mitochondrial permeability transition pore (mPTP), the release of cytochrome c, and DNA fragmentation, all markers of apoptosis [69,85]. Training exercises may reduce the mitochondrial release of proapoptotic proteins and the resultant DNA fragmentation [86,87]. Mitochondrial dysfunction may also induce a caspase-independent apoptotic pathway that contributes to the disruption of muscle quality in aging [88]. The calcium retention capacity was shown to be reduced in skeletal muscle mitochondria from old men, indicating mPTP sensitization to apoptosis [85]. Thus, mitochondria-dependent apoptosis in skeletal muscle represents a potential therapeutic target to counterbalance sarcopenia, as suggested by both in vitro and ex vivo studies [89,90].

3.3. Age-Dependent Alterations in Skeletal Muscle Mitochondria Biogenesis and Mitophagy

Alterations in skeletal muscle quality are also dependent on changes in mitochondrial biogenesis. Mitochondrial homeostasis in skeletal muscle is under the control of the peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, the master regulator of mitochondrial biogenesis, which is promoted by contractile activity and induces the switching from glycolytic toward oxidative fibers [91]. Nevertheless, an age-dependent decrease in mitochondrial biogenesis may be sustained by the defective response of PGC-1α to exercise [92]. The decreased mitochondrial content in old skeletal muscle may also be dependent on lower PGC-1α expression, which has been described both in slow- and in fast-twitch fibers [54,57,66]. Nevertheless, other studies have described opposite results related to the expression level of the mitochondrial transcription factor A (Tfam), a downstream main PGC-1α transcription factor, in old skeletal muscle [93,94,95].
The limited capacity of senescent skeletal muscle cells to remove injured mitochondria (mitophagy) could be a further cause of mitochondrial alteration. Nevertheless, studies on skeletal muscle from rodents show debated results on mitophagy modulators [96,97,98]. PGC-1α overexpression in skeletal muscle inhibits mitophagy, which appears enhanced in aging [96]. Genes related to mitophagy were described as downregulated in a cross-sectional study on physically inactive frail old women [99]. On the contrary, mitophagy and its regulatory proteins were increased in rodent models of sarcopenia [100,101]. Another study indicated that lysosomal dysfunction may cause an accumulation of disrupted mitochondria in the skeletal muscle of old mice [102]. The muscle-specific deletion of the Mtf2 gene in mice alters autophagy and triggers an adaptive mitochondrial quality control pathway [103]. Controversial results on mitophagy in sarcopenia suggest the need for further research, since this could be a potential therapeutic target. Indeed, the overexpression of the mitophagy regulator Parkin in skeletal muscle attenuates sarcopenia by enhancing mitochondrial content and function [104].

4. Muscle Mitochondria-Targeted Therapy for the Management of Sarcopenia

4.1. Mitochondria-Targeted Delivery Systems

Mitochondrial delivery strategies can be classified either as referring to the molecular size and type or considering the molecular mechanism [105,106]. According to the first, the best strategy to target mitochondria for the treatment of sarcopenia consists of the use of 1–1000 nm sized particles, which can directly trigger myotubes or inflammatory cells [107,108,109]. According to the latter, passive and active mechanisms are described. Passive targeting relies on the physical and chemical properties of carrier systems, while active targeting refers to specific interactions (ligand–receptor or antigen–antibody) at mitochondrial sites (Figure 2) [110].

4.1.1. Passive Delivery

Several small-sized compounds can be highly localized within mitochondria because of their biochemical and biophysical features (lipophilicity and/or positive charge). Classified as delocalized lipophilic cations (DLCs), these compounds easily cross mitochondrial membranes and locate in the matrix. DLCs include tetraphenylphosphonium (TPP+) or its methylated form (TPMP+), dequalinium (DQA), and guanidine [110]. DLCs are conjugated to deliver antioxidant compounds, to selectively transport DNA or anticancer agents, sorbitol, metals, and copolymers [110]. Even though DLCs allow for the mitochondrial administration of a specific drug dose, preventing toxicity and resistance, their delivery is limited to electrically neutral and very small conjugates, together with an increased risk of depolarization [10]. Szeto–Schiller (SS) peptides are cell-permeable short peptides (less than 10 amino acids) with antioxidant properties, whose cellular uptake is only dependent on concentration, but not on an electric charge, preventing the risk of depolarization [111]. Liposomes are spherical compounds consisting of phosphatidylglycerol, phosphatidylcholine, and cholesterol, with a hydrophilic core surrounded by a lipid bilayer [112]. Liposomes are nontoxic and can deliver large-sized drugs, including antioxidants, mitochondria-targeted molecules, or even mtDNA [113,114].

4.1.2. Active Delivery

A different strategy to deliver compounds within mitochondria consists of the use of peptides, which are specifically recognized by signal sequences and cleaved off after effective import.
Cell-penetrating peptides (CPPs), such as R8 (RRRRRRRR) and TAT (RKKRRQRRR), are used to enhance the delivery of oligonucleotides, peptides, proteins, and liposomes [115,116].
Mitochondria signal peptides (MSPs) or mitochondria-targeting sequences (MTSs) are normally used to import proteins synthetized in ribosomes within mitochondria [117]. These MSPs or MTSs can be conjugated to nonmitochondrial compounds to form chimeric molecules that are specifically recognized by mitochondrial import machinery, selectively delivering to the intermembrane space, inner membrane, or matrix [117].
Mitochondria-penetrating peptides (MPPs) are artificial compounds based on a CPP strategy, but enriched with positively charged peptides and extra lipophilic amino acids that can efficiently cross the mitochondrial bilayer and interact with the inner mitochondrial membrane [118]. Indeed, compounds covalently conjugated to MMPs are able to mostly accumulate in mitochondria rather than the cytoplasm or nucleus [119].

4.2. Mitochondria-Targeted Therapy in Muscle Tissue

To date, exercise is the sole proven therapy for sarcopenia, since it can limit modifications induced by muscle aging [120,121,122]. Nevertheless, several sarcopenic patients are not able to exercise because of clinical complications and/or protracted immobilization. Consequently, the development of compounds that limit the loss of skeletal muscle mass and function is strongly encouraged. To be significantly effective, these compounds should be conveyed using a suitable drug delivery system. A main determinant strategy for developing such compounds is muscle-targeting delivery systems. Among examples of muscle-targeting peptides, the heptapeptide sequence ASSLNIA improves the specificity for binding to skeletal muscle by screening a random phage display library [123]. The 5-polyamidoamine dendrimer (G5-PAMAM) modified with ASSLNIA may synergistically improve skeletal muscle gene delivery [124]. The 12-mer peptide M12, which increases the binding affinity to myoblasts, conjugated with phosphorodiamidate morpholino oligomers may improve muscle function [125].
A promising approach to boost mitochondrial function in muscles consists of increasing intracellular NAD+ by inhibiting enzymes that deplete its intracellular levels. The prolonged utilization of MRL-45696, a dual inhibitor of poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2, which consume NAD+), improves mitochondrial function in mouse skeletal muscle [126]. The nicotinic acid derivative acipimox, an NAD+ precursor, is able to directly enhance skeletal muscle mitochondrial function in humans [127].
Evidence on the efficacy of mitochondria-targeted drug delivery in skeletal muscle was provided in several preclinical studies. Mitoquinone Q, a mitochondria-targeted antioxidant, was able to improve muscle strength and mass in a murine model of cancer cachexia, stimulating beta-oxidation and promoting a shift from glycolytic to oxidative metabolism in muscle fibers [128]. Mito-TEMPOL, a mitochondria-targeted superoxide dismutase mimetic, prevents muscle weakness and wasting via the improvement in mitochondrial function in models of sepsis and uremia [129,130]. The mitochondria-targeted Szeto–Schiller peptide SS-31 was shown to improve exercise tolerance by increasing mitochondrial quality without mitochondrial content in aged mice [131].

5. Conclusions and Perspectives

Mitochondria are the most important cellular generators of energy, but also the main source of reactive species. Furthermore, mitochondria regulate cell death. The significance of mitochondrial alterations in the pathogenesis of sarcopenia is sustained through solid investigations, so that these organelles remain attractive therapeutic targets.
Innovative pharmacology is able to produce molecules that can modulate mitochondria in several ways. Compounds can actively or passively enter mitochondria and act as scavengers or substitute molecules. However, several of these molecules need to be tested in vivo for the treatment of sarcopenia. Preclinical experiments strongly advise for their potential efficacy in preserving mitochondrial quality and function, counterbalancing oxidative stress and preventing mitochondrial apoptosis. The development of molecules targeted to skeletal muscle mitochondria could overwhelm several challenges associated with actual therapies, increasing the efficacy and decreasing toxicity. Even though mitochondrial medicine is developing, current applications in the treatment of sarcopenia support future clinical studies.

Author Contributions

Writing—original draft preparation, F.B. and A.L.B.; writing—review and editing, G.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Rosenberg, I.H. Sarcopenia: Origins and clinical relevance. J. Nutr. 1997, 127, 990S–991S. [Google Scholar] [CrossRef] [Green Version]
  2. Cruz-Jentoft, A.J.; Bahat, G.; Bauer, J.; Boirie, Y.; Bruyere, O.; Cederholm, T.; Cooper, C.; Landi, F.; Rolland, Y.; Sayer, A.A.; et al. Sarcopenia: Revised European consensus on definition and diagnosis. Age Ageing 2019, 48, 601. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Dhillon, R.J.; Hasni, S. Pathogenesis and Management of Sarcopenia. Clin. Geriatr. Med. 2017, 33, 17–26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Jang, E.H.; Han, Y.J.; Jang, S.E.; Lee, S. Association between Diet Quality and Sarcopenia in Older Adults: Systematic Review of Prospective Cohort Studies. Life 2021, 11, 811. [Google Scholar] [CrossRef]
  5. Englund, D.A.; Zhang, X.; Aversa, Z.; LeBrasseur, N.K. Skeletal muscle aging, cellular senescence, and senotherapeutics: Current knowledge and future directions. Mech. Ageing Dev. 2021, 200, 111595. [Google Scholar] [CrossRef] [PubMed]
  6. Martone, A.M.; Marzetti, E.; Calvani, R.; Picca, A.; Tosato, M.; Bernabei, R.; Landi, F. Assessment of sarcopenia: From clinical practice to research. J. Gerontol. Geriatr. 2019, 67, 39–45. [Google Scholar]
  7. Koller, M. Sarcopenia-a geriatric pandemic: A narrative review. Wien. Med. Wochenschr. 2022. [Google Scholar] [CrossRef] [PubMed]
  8. Romanello, V.; Sandri, M. Mitochondrial Quality Control and Muscle Mass Maintenance. Front. Physiol. 2015, 6, 422. [Google Scholar] [CrossRef] [PubMed]
  9. Bellanti, F.; Lo Buglio, A.; Vendemiale, G. Mitochondrial Impairment in Sarcopenia. Biology 2021, 10, 31. [Google Scholar] [CrossRef] [PubMed]
  10. Armstrong, J.S. Mitochondrial medicine: Pharmacological targeting of mitochondria in disease. Br. J. Pharmacol. 2007, 151, 1154–1165. [Google Scholar] [CrossRef] [PubMed]
  11. Ebner, D.C.; Bialek, P.; El-Kattan, A.F.; Ambler, C.M.; Tu, M. Strategies for skeletal muscle targeting in drug discovery. Curr. Pharm. Des. 2015, 21, 1327–1336. [Google Scholar] [CrossRef] [PubMed]
  12. Evans, W.J. Skeletal muscle loss: Cachexia, sarcopenia, and inactivity. Am. J. Clin. Nutr. 2010, 91, 1123S–1127S. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Mitchell, W.K.; Williams, J.; Atherton, P.; Larvin, M.; Lund, J.; Narici, M. Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Front. Physiol. 2012, 3, 260. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Papadopoulou, S.K.; Tsintavis, P.; Potsaki, P.; Papandreou, D. Differences in the Prevalence of Sarcopenia in Community-Dwelling, Nursing Home and Hospitalized Individuals. A Systematic Review and Meta-Analysis. J. Nutr. Health Aging 2020, 24, 83–90. [Google Scholar] [CrossRef] [PubMed]
  15. Nawawi, A.; Justine, M.; Mazzuin Razali, R. Quality of life, hospitalisation and sarcopenia among the elderly: A sistematic review. J. Gerontol. Geriatr. 2021, 69, 45–52. [Google Scholar] [CrossRef]
  16. Westerblad, H.; Bruton, J.D.; Katz, A. Skeletal muscle: Energy metabolism, fiber types, fatigue and adaptability. Exp. Cell Res. 2010, 316, 3093–3099. [Google Scholar] [CrossRef] [PubMed]
  17. Biolo, G.; Cederholm, T.; Muscaritoli, M. Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: From sarcopenic obesity to cachexia. Clin. Nutr. 2014, 33, 737–748. [Google Scholar] [CrossRef]
  18. Gheller, B.J.; Riddle, E.S.; Lem, M.R.; Thalacker-Mercer, A.E. Understanding Age-Related Changes in Skeletal Muscle Metabolism: Differences between Females and Males. Annu. Rev. Nutr. 2016, 36, 129–156. [Google Scholar] [CrossRef] [PubMed]
  19. Marcus, R.L.; Addison, O.; Kidde, J.P.; Dibble, L.E.; Lastayo, P.C. Skeletal muscle fat infiltration: Impact of age, inactivity, and exercise. J. Nutr. Health Aging 2010, 14, 362–366. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Croley, A.N.; Zwetsloot, K.A.; Westerkamp, L.M.; Ryan, N.A.; Pendergast, A.M.; Hickner, R.C.; Pofahl, W.E.; Gavin, T.P. Lower capillarization, VEGF protein, and VEGF mRNA response to acute exercise in the vastus lateralis muscle of aged vs. young women. J. Appl. Physiol. 2005, 99, 1872–1879. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Coggan, A.R.; Spina, R.J.; King, D.S.; Rogers, M.A.; Brown, M.; Nemeth, P.M.; Holloszy, J.O. Histochemical and enzymatic comparison of the gastrocnemius muscle of young and elderly men and women. J. Gerontol. 1992, 47, B71–B76. [Google Scholar] [CrossRef]
  22. Proctor, D.N.; Sinning, W.E.; Walro, J.M.; Sieck, G.C.; Lemon, P.W. Oxidative capacity of human muscle fiber types: Effects of age and training status. J. Appl. Physiol. 1995, 78, 2033–2038. [Google Scholar] [CrossRef]
  23. Landers-Ramos, R.Q.; Prior, S.J. The Microvasculature and Skeletal Muscle Health in Aging. Exerc. Sport Sci. Rev. 2018, 46, 172–179. [Google Scholar] [CrossRef]
  24. Gaster, M.; Poulsen, P.; Handberg, A.; Schroder, H.D.; Beck-Nielsen, H. Direct evidence of fiber type-dependent GLUT-4 expression in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 2000, 278, E910–E916. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Murgia, M.; Toniolo, L.; Nagaraj, N.; Ciciliot, S.; Vindigni, V.; Schiaffino, S.; Reggiani, C.; Mann, M. Single Muscle Fiber Proteomics Reveals Fiber-Type-Specific Features of Human Muscle Aging. Cell Rep. 2017, 19, 2396–2409. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Consitt, L.A.; Dudley, C.; Saxena, G. Impact of Endurance and Resistance Training on Skeletal Muscle Glucose Metabolism in Older Adults. Nutrients 2019, 11, 2636. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Tucker, M.Z.; Turcotte, L.P. Impaired fatty acid oxidation in muscle of aging rats perfused under basal conditions. Am. J. Physiol. Endocrinol. Metab. 2002, 282, E1102–E1109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Tucker, M.Z.; Turcotte, L.P. Aging is associated with elevated muscle triglyceride content and increased insulin-stimulated fatty acid uptake. Am. J. Physiol. Endocrinol. Metab. 2003, 285, E827–E835. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Tieland, M.; Trouwborst, I.; Clark, B.C. Skeletal muscle performance and ageing. J. Cachexia Sarcopenia Muscle 2018, 9, 3–19. [Google Scholar] [CrossRef]
  30. Volpi, E.; Rasmussen, B.B. Nutrition and muscle protein metabolism in the elderly. Diabetes Nutr. Metab. 2000, 13, 99–107. [Google Scholar] [PubMed]
  31. Fry, C.S.; Rasmussen, B.B. Skeletal muscle protein balance and metabolism in the elderly. Curr. Aging Sci. 2011, 4, 260–268. [Google Scholar] [CrossRef]
  32. D’Angelo, E.; Marzetti, E.; Calvani, R.; Picca, A.; Tosato, M.; Bernabei, R.; Landi, F. Impact of physical activity on the management of sarcopenia. J. Gerontol. Geriatr. 2019, 67, 46–51. [Google Scholar]
  33. Volpi, E.; Sheffield-Moore, M.; Rasmussen, B.B.; Wolfe, R.R. Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA 2001, 286, 1206–1212. [Google Scholar] [CrossRef]
  34. Rennie, M.J. Anabolic resistance: The effects of aging, sexual dimorphism, and immobilization on human muscle protein turnover. Appl. Physiol. Nutr. Metab. 2009, 34, 377–381. [Google Scholar] [CrossRef] [PubMed]
  35. Cobley, J.N.; Sakellariou, G.K.; Murray, S.; Waldron, S.; Gregson, W.; Burniston, J.G.; Morton, J.P.; Iwanejko, L.A.; Close, G.L. Lifelong endurance training attenuates age-related genotoxic stress in human skeletal muscle. Longev. Healthspan 2013, 2, 11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Cobley, J.N.; Sakellariou, G.K.; Owens, D.J.; Murray, S.; Waldron, S.; Gregson, W.; Fraser, W.D.; Burniston, J.G.; Iwanejko, L.A.; McArdle, A.; et al. Lifelong training preserves some redox-regulated adaptive responses after an acute exercise stimulus in aged human skeletal muscle. Free Radic. Biol. Med. 2014, 70, 23–32. [Google Scholar] [CrossRef]
  37. Fernando, R.; Drescher, C.; Nowotny, K.; Grune, T.; Castro, J.P. Impaired proteostasis during skeletal muscle aging. Free Radic. Biol. Med. 2019, 132, 58–66. [Google Scholar] [CrossRef]
  38. Scott, W.; Stevens, J.; Binder-Macleod, S.A. Human skeletal muscle fiber type classifications. Phys. Ther. 2001, 81, 1810–1816. [Google Scholar] [CrossRef] [PubMed]
  39. Lexell, J.; Taylor, C.C.; Sjostrom, M. What is the cause of the ageing atrophy? Total number, size and proportion of different fiber types studied in whole vastus lateralis muscle from 15- to 83-year-old men. J. Neurol. Sci. 1988, 84, 275–294. [Google Scholar] [CrossRef] [PubMed]
  40. Wilkinson, D.J.; Piasecki, M.; Atherton, P.J. The age-related loss of skeletal muscle mass and function: Measurement and physiology of muscle fibre atrophy and muscle fibre loss in humans. Ageing Res. Rev. 2018, 47, 123–132. [Google Scholar] [CrossRef] [PubMed]
  41. Beavers, K.M.; Beavers, D.P.; Houston, D.K.; Harris, T.B.; Hue, T.F.; Koster, A.; Newman, A.B.; Simonsick, E.M.; Studenski, S.A.; Nicklas, B.J.; et al. Associations between body composition and gait-speed decline: Results from the Health, Aging, and Body Composition study. Am. J. Clin. Nutr. 2013, 97, 552–560. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Cholok, D.; Lee, E.; Lisiecki, J.; Agarwal, S.; Loder, S.; Ranganathan, K.; Qureshi, A.T.; Davis, T.A.; Levi, B. Traumatic muscle fibrosis: From pathway to prevention. J. Trauma Acute Care Surg. 2017, 82, 174–184. [Google Scholar] [CrossRef] [PubMed]
  43. D’Antona, G.; Pellegrino, M.A.; Adami, R.; Rossi, R.; Carlizzi, C.N.; Canepari, M.; Saltin, B.; Bottinelli, R. The effect of ageing and immobilization on structure and function of human skeletal muscle fibres. J. Physiol. 2003, 552, 499–511. [Google Scholar] [CrossRef]
  44. Kragstrup, T.W.; Kjaer, M.; Mackey, A.L. Structural, biochemical, cellular, and functional changes in skeletal muscle extracellular matrix with aging. Scand. J. Med. Sci. Sports 2011, 21, 749–757. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Landi, F.; Camprubi-Robles, M.; Bear, D.E.; Cederholm, T.; Malafarina, V.; Welch, A.A.; Cruz-Jentoft, A.J. Muscle loss: The new malnutrition challenge in clinical practice. Clin. Nutr. 2019, 38, 2113–2120. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. McGregor, R.A.; Cameron-Smith, D.; Poppitt, S.D. It is not just muscle mass: A review of muscle quality, composition and metabolism during ageing as determinants of muscle function and mobility in later life. Longev. Healthspan 2014, 3, 9. [Google Scholar] [CrossRef] [Green Version]
  47. Narici, M.V.; Maffulli, N. Sarcopenia: Characteristics, mechanisms and functional significance. Br. Med. Bull. 2010, 95, 139–159. [Google Scholar] [CrossRef] [Green Version]
  48. Narici, M.V.; Maganaris, C.N.; Reeves, N.D.; Capodaglio, P. Effect of aging on human muscle architecture. J. Appl. Physiol. 2003, 95, 2229–2234. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Thom, J.M.; Morse, C.I.; Birch, K.M.; Narici, M.V. Influence of muscle architecture on the torque and power-velocity characteristics of young and elderly men. Eur. J. Appl. Physiol. 2007, 100, 613–619. [Google Scholar] [CrossRef]
  50. Lopez-Otin, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. The hallmarks of aging. Cell 2013, 153, 1194–1217. [Google Scholar] [CrossRef] [Green Version]
  51. Cogswell, A.M.; Stevens, R.J.; Hood, D.A. Properties of skeletal muscle mitochondria isolated from subsarcolemmal and intermyofibrillar regions. Am. J. Physiol. 1993, 264, C383–C389. [Google Scholar] [CrossRef] [PubMed]
  52. Hood, D.A. Invited Review: Contractile activity-induced mitochondrial biogenesis in skeletal muscle. J. Appl. Physiol. 2001, 90, 1137–1157. [Google Scholar] [CrossRef] [PubMed]
  53. Picard, M.; White, K.; Turnbull, D.M. Mitochondrial morphology, topology, and membrane interactions in skeletal muscle: A quantitative three-dimensional electron microscopy study. J. Appl. Physiol. 2013, 114, 161–171. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Beregi, E.; Regius, O.; Huttl, T.; Gobl, Z. Age-related changes in the skeletal muscle cells. Z. Gerontol. 1988, 21, 83–86. [Google Scholar] [PubMed]
  55. Iqbal, S.; Ostojic, O.; Singh, K.; Joseph, A.M.; Hood, D.A. Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse. Muscle Nerve 2013, 48, 963–970. [Google Scholar] [CrossRef]
  56. Callahan, D.M.; Toth, M.J. Skeletal muscle protein metabolism in human heart failure. Curr. Opin. Clin. Nutr. Metab. Care 2013, 16, 66–71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Joseph, A.M.; Adhihetty, P.J.; Buford, T.W.; Wohlgemuth, S.E.; Lees, H.A.; Nguyen, L.M.; Aranda, J.M.; Sandesara, B.D.; Pahor, M.; Manini, T.M.; et al. The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals. Aging Cell 2012, 11, 801–809. [Google Scholar] [CrossRef] [Green Version]
  58. Joseph, A.M.; Adhihetty, P.J.; Wawrzyniak, N.R.; Wohlgemuth, S.E.; Picca, A.; Kujoth, G.C.; Prolla, T.A.; Leeuwenburgh, C. Dysregulation of mitochondrial quality control processes contribute to sarcopenia in a mouse model of premature aging. PLoS ONE 2013, 8, e69327. [Google Scholar] [CrossRef] [Green Version]
  59. Leduc-Gaudet, J.P.; Auger, M.J.; St Jean, P.F.; Gouspillou, G. Towards a better understanding of the role played by mitochondrial dynamics and morphology in skeletal muscle atrophy. J. Physiol. 2015, 593, 2993–2994. [Google Scholar] [CrossRef] [Green Version]
  60. Picca, A.; Calvani, R.; Lorenzi, M.; Menghi, A.; Galli, M.; Vitiello, R.; Randisi, F.; Bernabei, R.; Landi, F.; Marzetti, E. Mitochondrial dynamics signaling is shifted toward fusion in muscles of very old hip-fractured patients: Results from the Sarcopenia in HIp FracTure (SHIFT) exploratory study. Exp. Gerontol. 2017, 96, 63–67. [Google Scholar] [CrossRef] [PubMed]
  61. Correia-Melo, C.; Ichim, G.; Tait, S.W.; Passos, J.F. Depletion of mitochondria in mammalian cells through enforced mitophagy. Nat. Protoc. 2017, 12, 183–194. [Google Scholar] [CrossRef] [Green Version]
  62. Favaro, G.; Romanello, V.; Varanita, T.; Andrea, D.M.; Morbidoni, V.; Tezze, C.; Albiero, M.; Canato, M.; Gherardi, G.; De, S.D.; et al. DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass. Nat. Commun. 2019, 10, 2576. [Google Scholar] [CrossRef]
  63. Marzetti, E.; Calvani, R.; Cesari, M.; Buford, T.W.; Lorenzi, M.; Behnke, B.J.; Leeuwenburgh, C. Mitochondrial dysfunction and sarcopenia of aging: From signaling pathways to clinical trials. Int. J. Biochem. Cell Biol. 2013, 45, 2288–2301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Marzetti, E.; Leeuwenburgh, C. Skeletal muscle apoptosis, sarcopenia and frailty at old age. Exp. Gerontol. 2006, 41, 1234–1238. [Google Scholar] [CrossRef] [PubMed]
  65. Boffoli, D.; Scacco, S.C.; Vergari, R.; Solarino, G.; Santacroce, G.; Papa, S. Decline with age of the respiratory chain activity in human skeletal muscle. Biochim. Biophys. Acta 1994, 1226, 73–82. [Google Scholar] [CrossRef] [PubMed]
  66. Rooyackers, O.E.; Adey, D.B.; Ades, P.A.; Nair, K.S. Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle. Proc. Natl. Acad. Sci. USA 1996, 93, 15364–15369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Short, K.R.; Bigelow, M.L.; Kahl, J.; Singh, R.; Coenen-Schimke, J.; Raghavakaimal, S.; Nair, K.S. Decline in skeletal muscle mitochondrial function with aging in humans. Proc. Natl. Acad. Sci. USA 2005, 102, 5618–5623. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Marcinek, D.J.; Schenkman, K.A.; Ciesielski, W.A.; Lee, D.; Conley, K.E. Reduced mitochondrial coupling in vivo alters cellular energetics in aged mouse skeletal muscle. J. Physiol. 2005, 569, 467–473. [Google Scholar] [CrossRef] [PubMed]
  69. Chabi, B.; Ljubicic, V.; Menzies, K.J.; Huang, J.H.; Saleem, A.; Hood, D.A. Mitochondrial function and apoptotic susceptibility in aging skeletal muscle. Aging Cell 2008, 7, 2–12. [Google Scholar] [CrossRef] [PubMed]
  70. Kent-Braun, J.A.; Ng, A.V. Skeletal muscle oxidative capacity in young and older women and men. J. Appl. Physiol. 2000, 89, 1072–1078. [Google Scholar] [CrossRef]
  71. Picard, M.; Ritchie, D.; Thomas, M.M.; Wright, K.J.; Hepple, R.T. Alterations in intrinsic mitochondrial function with aging are fiber type-specific and do not explain differential atrophy between muscles. Aging Cell 2011, 10, 1047–1055. [Google Scholar] [CrossRef] [PubMed]
  72. Johnson, M.L.; Robinson, M.M.; Nair, K.S. Skeletal muscle aging and the mitochondrion. Trends Endocrinol. Metab. 2013, 24, 247–256. [Google Scholar] [CrossRef] [PubMed]
  73. Cento, A.S.; Leigheb, M.; Caretti, G.; Penna, F. Exercise and Exercise Mimetics for the Treatment of Musculoskeletal Disorders. Curr. Osteoporos. Rep. 2022, 20, 249–259. [Google Scholar] [CrossRef] [PubMed]
  74. Carter, H.N.; Chen, C.C.; Hood, D.A. Mitochondria, muscle health, and exercise with advancing age. Physiology 2015, 30, 208–223. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Liu, D.; Sartor, M.A.; Nader, G.A.; Pistilli, E.E.; Tanton, L.; Lilly, C.; Gutmann, L.; IglayReger, H.B.; Visich, P.S.; Hoffman, E.P.; et al. Microarray analysis reveals novel features of the muscle aging process in men and women. J. Gerontol. A Biol. Sci. Med. Sci. 2013, 68, 1035–1044. [Google Scholar] [CrossRef] [Green Version]
  76. Bua, E.A.; McKiernan, S.H.; Wanagat, J.; McKenzie, D.; Aiken, J.M. Mitochondrial abnormalities are more frequent in muscles undergoing sarcopenia. J. Appl. Physiol. 2002, 92, 2617–2624. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Aiken, J.; Bua, E.; Cao, Z.; Lopez, M.; Wanagat, J.; McKenzie, D.; McKiernan, S. Mitochondrial DNA deletion mutations and sarcopenia. Ann. NY Acad. Sci. 2002, 959, 412–423. [Google Scholar] [CrossRef] [PubMed]
  78. McKenzie, D.; Bua, E.; McKiernan, S.; Cao, Z.; Aiken, J.M. Mitochondrial DNA deletion mutations: A causal role in sarcopenia. Eur. J. Biochem. 2002, 269, 2010–2015. [Google Scholar] [CrossRef] [PubMed]
  79. McKiernan, S.H.; Colman, R.; Lopez, M.; Beasley, T.M.; Weindruch, R.; Aiken, J.M. Longitudinal analysis of early stage sarcopenia in aging rhesus monkeys. Exp. Gerontol. 2009, 44, 170–176. [Google Scholar] [CrossRef] [Green Version]
  80. Safdar, A.; Hamadeh, M.J.; Kaczor, J.J.; Raha, S.; deBeer, J.; Tarnopolsky, M.A. Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults. PLoS ONE 2010, 5, e10778. [Google Scholar] [CrossRef] [PubMed]
  81. Dodds, R.M.; Davies, K.; Granic, A.; Hollingsworth, K.G.; Warren, C.; Gorman, G.; Turnbull, D.M.; Sayer, A.A. Mitochondrial respiratory chain function and content are preserved in the skeletal muscle of active very old men and women. Exp. Gerontol. 2018, 113, 80–85. [Google Scholar] [CrossRef]
  82. Hiona, A.; Sanz, A.; Kujoth, G.C.; Pamplona, R.; Seo, A.Y.; Hofer, T.; Someya, S.; Miyakawa, T.; Nakayama, C.; Samhan-Arias, A.K.; et al. Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice. PLoS ONE 2010, 5, e11468. [Google Scholar] [CrossRef]
  83. Rygiel, K.A.; Grady, J.P.; Turnbull, D.M. Respiratory chain deficiency in aged spinal motor neurons. Neurobiol. Aging 2014, 35, 2230–2238. [Google Scholar] [CrossRef] [Green Version]
  84. Pollock, N.; Staunton, C.A.; Vasilaki, A.; McArdle, A.; Jackson, M.J. Denervated muscle fibers induce mitochondrial peroxide generation in neighboring innervated fibers: Role in muscle aging. Free Radic. Biol. Med. 2017, 112, 84–92. [Google Scholar] [CrossRef] [PubMed]
  85. Gouspillou, G.; Sgarioto, N.; Kapchinsky, S.; Purves-Smith, F.; Norris, B.; Pion, C.H.; Barbat-Artigas, S.; Lemieux, F.; Taivassalo, T.; Morais, J.A.; et al. Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans. FASEB J. 2014, 28, 1621–1633. [Google Scholar] [CrossRef] [PubMed]
  86. Song, W.; Kwak, H.B.; Lawler, J.M. Exercise training attenuates age-induced changes in apoptotic signaling in rat skeletal muscle. Antioxid. Redox Signal. 2006, 8, 517–528. [Google Scholar] [CrossRef] [PubMed]
  87. Adhihetty, P.J.; Taivassalo, T.; Haller, R.G.; Walkinshaw, D.R.; Hood, D.A. The effect of training on the expression of mitochondrial biogenesis- and apoptosis-related proteins in skeletal muscle of patients with mtDNA defects. Am. J. Physiol. Endocrinol. Metab. 2007, 293, E672–E680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Otera, H.; Mihara, K. Molecular mechanisms and physiologic functions of mitochondrial dynamics. J. Biochem. 2011, 149, 241–251. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Salucci, S.; Battistelli, M.; Baldassarri, V.; Burini, D.; Falcieri, E.; Burattini, S. Melatonin prevents mitochondrial dysfunctions and death in differentiated skeletal muscle cells. Microsc. Res. Tech. 2017, 80, 1174–1181. [Google Scholar] [CrossRef] [PubMed]
  90. Sayed, R.K.A.; Fernandez-Ortiz, M.; Diaz-Casado, M.E.; Rusanova, I.; Rahim, I.; Escames, G.; Lopez, L.C.; Mokhtar, D.M.; Acuna-Castroviejo, D. The Protective Effect of Melatonin against Age-Associated, Sarcopenia-Dependent Tubular Aggregate Formation, Lactate Depletion, and Mitochondrial Changes. J. Gerontol. A Biol. Sci. Med. Sci. 2018, 73, 1330–1338. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Akimoto, T.; Pohnert, S.C.; Li, P.; Zhang, M.; Gumbs, C.; Rosenberg, P.B.; Williams, R.S.; Yan, Z. Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J. Biol. Chem. 2005, 280, 19587–19593. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Derbre, F.; Gomez-Cabrera, M.C.; Nascimento, A.L.; Sanchis-Gomar, F.; Martinez-Bello, V.E.; Tresguerres, J.A.; Fuentes, T.; Gratas-Delamarche, A.; Monsalve, M.; Vina, J. Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1alpha to exercise training. Age 2012, 34, 669–679. [Google Scholar] [CrossRef]
  93. Lezza, A.M.; Pesce, V.; Cormio, A.; Fracasso, F.; Vecchiet, J.; Felzani, G.; Cantatore, P.; Gadaleta, M.N. Increased expression of mitochondrial transcription factor A and nuclear respiratory factor-1 in skeletal muscle from aged human subjects. FEBS Lett. 2001, 501, 74–78. [Google Scholar] [CrossRef]
  94. Masuyama, M.; Iida, R.; Takatsuka, H.; Yasuda, T.; Matsuki, T. Quantitative change in mitochondrial DNA content in various mouse tissues during aging. Biochim. Biophys. Acta 2005, 1723, 302–308. [Google Scholar] [CrossRef] [PubMed]
  95. Pesce, V.; Cormio, A.; Fracasso, F.; Lezza, A.M.; Cantatore, P.; Gadaleta, M.N. Age-related changes of mitochondrial DNA content and mitochondrial genotypic and phenotypic alterations in rat hind-limb skeletal muscles. J. Gerontol. A Biol. Sci. Med. Sci. 2005, 60, 715–723. [Google Scholar] [CrossRef] [Green Version]
  96. Yeo, D.; Kang, C.; Gomez-Cabrera, M.C.; Vina, J.; Ji, L.L. Intensified mitophagy in skeletal muscle with aging is downregulated by PGC-1alpha overexpression in vivo. Free Radic. Biol. Med. 2019, 130, 361–368. [Google Scholar] [CrossRef]
  97. Herbst, A.; Lee, C.C.; Vandiver, A.R.; Aiken, J.M.; McKenzie, D.; Hoang, A.; Allison, D.; Liu, N.; Wanagat, J. Mitochondrial DNA deletion mutations increase exponentially with age in human skeletal muscle. Aging Clin. Exp. Res. 2021, 33, 1811–1820. [Google Scholar] [CrossRef] [PubMed]
  98. Kim, C.; Hwang, J.K. The 5,7-Dimethoxyflavone Suppresses Sarcopenia by Regulating Protein Turnover and Mitochondria Biogenesis-Related Pathways. Nutrients 2020, 12, 1079. [Google Scholar] [CrossRef] [PubMed]
  99. Drummond, M.J.; Addison, O.; Brunker, L.; Hopkins, P.N.; McClain, D.A.; Lastayo, P.C.; Marcus, R.L. Downregulation of E3 ubiquitin ligases and mitophagy-related genes in skeletal muscle of physically inactive, frail older women: A cross-sectional comparison. J. Gerontol. A Biol. Sci. Med. Sci. 2014, 69, 1040–1048. [Google Scholar] [CrossRef] [PubMed]
  100. Chen, C.C.W.; Erlich, A.T.; Crilly, M.J.; Hood, D.A. Parkin is required for exercise-induced mitophagy in muscle: Impact of aging. Am. J. Physiol. Endocrinol. Metab. 2018, 315, E404–E415. [Google Scholar] [CrossRef]
  101. Carter, H.N.; Kim, Y.; Erlich, A.T.; Zarrin-Khat, D.; Hood, D.A. Autophagy and mitophagy flux in young and aged skeletal muscle following chronic contractile activity. J. Physiol. 2018, 596, 3567–3584. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. O’Leary, M.F.; Vainshtein, A.; Iqbal, S.; Ostojic, O.; Hood, D.A. Adaptive plasticity of autophagic proteins to denervation in aging skeletal muscle. Am. J. Physiol. Cell Physiol. 2013, 304, C422–C430. [Google Scholar] [CrossRef] [PubMed]
  103. Sebastian, D.; Sorianello, E.; Segales, J.; Irazoki, A.; Ruiz-Bonilla, V.; Sala, D.; Planet, E.; Berenguer-Llergo, A.; Munoz, J.P.; Sanchez-Feutrie, M.; et al. Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway. EMBO J. 2016, 35, 1677–1693. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Leduc-Gaudet, J.P.; Reynaud, O.; Hussain, S.N.; Gouspillou, G. Parkin overexpression protects from ageing-related loss of muscle mass and strength. J. Physiol. 2019, 597, 1975–1991. [Google Scholar] [CrossRef]
  105. Yamada, Y.; Harashima, H. Mitochondrial drug delivery systems for macromolecule and their therapeutic application to mitochondrial diseases. Adv. Drug Deliv. Rev. 2008, 60, 1439–1462. [Google Scholar] [CrossRef] [PubMed]
  106. Fulda, S.; Galluzzi, L.; Kroemer, G. Targeting mitochondria for cancer therapy. Nat. Rev. Drug Discov. 2010, 9, 447–464. [Google Scholar] [CrossRef] [PubMed]
  107. Raimondo, T.M.; Mooney, D.J. Functional muscle recovery with nanoparticle-directed M2 macrophage polarization in mice. Proc. Natl. Acad. Sci. USA 2018, 115, 10648–10653. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Guglielmi, V.; Carton, F.; Vattemi, G.; Arpicco, S.; Stella, B.; Berlier, G.; Marengo, A.; Boschi, F.; Malatesta, M. Uptake and intracellular distribution of different types of nanoparticles in primary human myoblasts and myotubes. Int. J. Pharm. 2019, 560, 347–356. [Google Scholar] [CrossRef] [PubMed]
  109. Maretti, E.; Molinari, S.; Battini, R.; Rustichelli, C.; Truzzi, E.; Iannuccelli, V.; Leo, E. Design, Characterization, and In Vitro Assays on Muscle Cells of Endocannabinoid-like Molecule Loaded Lipid Nanoparticles for a Therapeutic Anti-Inflammatory Approach to Sarcopenia. Pharmaceutics 2022, 14, 648. [Google Scholar] [CrossRef] [PubMed]
  110. Serviddio, G.; Bellanti, F.; Sastre, J.; Vendemiale, G.; Altomare, E. Targeting mitochondria: A new promising approach for the treatment of liver diseases. Curr. Med. Chem. 2010, 17, 2325–2337. [Google Scholar] [CrossRef] [PubMed]
  111. Szeto, H.H. Cell-permeable, mitochondrial-targeted, peptide antioxidants. AAPS J. 2006, 8, E277–E283. [Google Scholar] [CrossRef] [PubMed]
  112. Akbarzadeh, A.; Rezaei-Sadabady, R.; Davaran, S.; Joo, S.W.; Zarghami, N.; Hanifehpour, Y.; Samiei, M.; Kouhi, M.; Nejati-Koshki, K. Liposome: Classification, preparation, and applications. Nanoscale Res. Lett. 2013, 8, 102. [Google Scholar] [CrossRef]
  113. Yamada, Y.; Harashima, H. Delivery of bioactive molecules to the mitochondrial genome using a membrane-fusing, liposome-based carrier, DF-MITO-Porter. Biomaterials 2012, 33, 1589–1595. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Wongrakpanich, A.; Geary, S.M.; Joiner, M.L.; Anderson, M.E.; Salem, A.K. Mitochondria-targeting particles. Nanomedicine 2014, 9, 2531–2543. [Google Scholar] [CrossRef] [Green Version]
  115. Torchilin, V.P.; Rammohan, R.; Weissig, V.; Levchenko, T.S. TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. Proc. Natl. Acad. Sci. USA 2001, 98, 8786–8791. [Google Scholar] [CrossRef] [Green Version]
  116. Joliot, A.; Prochiantz, A. Transduction peptides: From technology to physiology. Nat. Cell Biol. 2004, 6, 189–196. [Google Scholar] [CrossRef] [PubMed]
  117. Lu, P.; Bruno, B.J.; Rabenau, M.; Lim, C.S. Delivery of drugs and macromolecules to the mitochondria for cancer therapy. J. Control. Release 2016, 240, 38–51. [Google Scholar] [CrossRef] [Green Version]
  118. Horton, K.L.; Stewart, K.M.; Fonseca, S.B.; Guo, Q.; Kelley, S.O. Mitochondria-penetrating peptides. Chem. Biol. 2008, 15, 375–382. [Google Scholar] [CrossRef] [Green Version]
  119. Chamberlain, G.R.; Tulumello, D.V.; Kelley, S.O. Targeted delivery of doxorubicin to mitochondria. ACS Chem. Biol. 2013, 8, 1389–1395. [Google Scholar] [CrossRef]
  120. Landi, F.; Marzetti, E.; Martone, A.M.; Bernabei, R.; Onder, G. Exercise as a remedy for sarcopenia. Curr. Opin. Clin. Nutr. Metab. Care 2014, 17, 25–31. [Google Scholar] [CrossRef] [PubMed]
  121. Phu, S.; Boersma, D.; Duque, G. Exercise and Sarcopenia. J. Clin. Densitom. 2015, 18, 488–492. [Google Scholar] [CrossRef]
  122. Yoo, S.Z.; No, M.H.; Heo, J.W.; Park, D.H.; Kang, J.H.; Kim, S.H.; Kwak, H.B. Role of exercise in age-related sarcopenia. J. Exerc. Rehabil. 2018, 14, 551–558. [Google Scholar] [CrossRef] [PubMed]
  123. Samoylova, T.I.; Smith, B.F. Elucidation of muscle-binding peptides by phage display screening. Muscle Nerve 1999, 22, 460–466. [Google Scholar] [CrossRef]
  124. Jativa, S.D.; Thapar, N.; Broyles, D.; Dikici, E.; Daftarian, P.; Jimenez, J.J.; Daunert, S.; Deo, S.K. Enhanced Delivery of Plasmid DNA to Skeletal Muscle Cells using a DLC8-Binding Peptide and ASSLNIA-Modified PAMAM Dendrimer. Mol. Pharm. 2019, 16, 2376–2384. [Google Scholar] [CrossRef] [PubMed]
  125. Gao, X.; Zhao, J.; Han, G.; Zhang, Y.; Dong, X.; Cao, L.; Wang, Q.; Moulton, H.M.; Yin, H. Effective dystrophin restoration by a novel muscle-homing peptide-morpholino conjugate in dystrophin-deficient mdx mice. Mol. Ther. 2014, 22, 1333–1341. [Google Scholar] [CrossRef] [Green Version]
  126. Pirinen, E.; Canto, C.; Jo, Y.S.; Morato, L.; Zhang, H.; Menzies, K.J.; Williams, E.G.; Mouchiroud, L.; Moullan, N.; Hagberg, C.; et al. Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle. Cell Metab. 2014, 19, 1034–1041. [Google Scholar] [CrossRef] [Green Version]
  127. van de Weijer, T.; Phielix, E.; Bilet, L.; Williams, E.G.; Ropelle, E.R.; Bierwagen, A.; Livingstone, R.; Nowotny, P.; Sparks, L.M.; Paglialunga, S.; et al. Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans. Diabetes 2015, 64, 1193–1201. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Pin, F.; Huot, J.R.; Bonetto, A. The Mitochondria-Targeting Agent MitoQ Improves Muscle Atrophy, Weakness and Oxidative Metabolism in C26 Tumor-Bearing Mice. Front. Cell Dev. Biol. 2022, 10, 861622. [Google Scholar] [CrossRef]
  129. Supinski, G.S.; Wang, L.; Schroder, E.A.; Callahan, L.A.P. MitoTEMPOL, a mitochondrial targeted antioxidant, prevents sepsis-induced diaphragm dysfunction. Am. J. Physiol. Lung Cell Mol. Physiol. 2020, 319, L228–L238. [Google Scholar] [CrossRef]
  130. Liu, Y.; Perumal, E.; Bi, X.; Wang, Y.; Ding, W. Potential mechanisms of uremic muscle wasting and the protective role of the mitochondria-targeted antioxidant Mito-TEMPO. Int. Urol. Nephrol. 2020, 52, 1551–1561. [Google Scholar] [CrossRef] [PubMed]
  131. Campbell, M.D.; Duan, J.; Samuelson, A.T.; Gaffrey, M.J.; Merrihew, G.E.; Egertson, J.D.; Wang, L.; Bammler, T.K.; Moore, R.J.; White, C.C.; et al. Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice. Free Radic. Biol. Med. 2019, 134, 268–281. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Age-associated altered metabolism in skeletal muscle.
Figure 1. Age-associated altered metabolism in skeletal muscle.
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Figure 2. Passive (up the dotted line) and active (down the dotted line) mitochondria delivery strategies.
Figure 2. Passive (up the dotted line) and active (down the dotted line) mitochondria delivery strategies.
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MDPI and ACS Style

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. https://doi.org/10.3390/pharmaceutics14122588

AMA Style

Bellanti F, Lo Buglio A, Vendemiale G. Muscle Delivery of Mitochondria-Targeted Drugs for the Treatment of Sarcopenia: Rationale and Perspectives. Pharmaceutics. 2022; 14(12):2588. https://doi.org/10.3390/pharmaceutics14122588

Chicago/Turabian Style

Bellanti, Francesco, Aurelio Lo Buglio, and Gianluigi Vendemiale. 2022. "Muscle Delivery of Mitochondria-Targeted Drugs for the Treatment of Sarcopenia: Rationale and Perspectives" Pharmaceutics 14, no. 12: 2588. https://doi.org/10.3390/pharmaceutics14122588

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