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Muscle Delivery of Mitochondria-Targeted Drugs for Sarcopenia
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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.

sarcopenia mitochondrial dysfunction oxidative stress
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Subjects: Gerontology
View Times: 44
Revisions: 2 times (View History)
Update Date: 05 Dec 2022
Table of Contents

    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, but most research suggests that modifications in mitochondrial biogenesis, morphology, function, and dynamics may represent the key process in disrupted muscle function and quality [[3]]. Progression in mitochondrial research and biomedical technology encourages the development of drugs specifically targeted to mitochondria for therapeutic use . Thus, researchers aim to stimulate the progression of muscle mitochondria-directed therapeutics for the management of sarcopenia.

    2. Mitochondrial Involvement in Sarcopenia

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

    Research on morphology in aged skeletal muscle describes giant mitochondria with disrupted cristae [4]. 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 [5]. 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 [6]. Morphological alterations in old skeletal muscle mitochondria may result from changes in mitochondrial dynamics, characterized by an imbalance that enhances fission rather than fusion [7]. Mitochondrial dynamics can be dysregulated by mtDNA mutations, since old mice expressing a defective mtDNA polymerase gamma exhibited enhanced mitochondrial fission in skeletal muscle [8]. Nevertheless, a higher mitochondrial fusion was described in skeletal muscle from old versus young mice [9]. A change toward mitochondrial fusion rather than fission was further described in the skeletal muscle of old hip-fractured patients [10]. A knock-out of fusion-related proteins (mitofusins, Mfn1/2) in skeletal muscle caused higher mtDNA mutations and tissue atrophy [11]. However, skeletal muscle degeneration and atrophy were described as a result of the deletion of the fission-related protein Drp1 [12]. Taken together, these studies suggest that modifications of mitochondrial dynamics in skeletal muscle and their commitment in sarcopenia need to be clarified.

    2.2. 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 [13]. Moreover, mitochondrial dysfunction triggers apoptosis, with a negative impact on skeletal muscle quality [14].
    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 [15][16][17][18][19]. However, it is worth noting that mitochondrial function in old skeletal muscle can be preserved with durable and intense physical activity [20][21][22]. 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 [23].
    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 [24]. 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 [25].
    In sarcopenia, mtDNA and mitochondrial electron transport chain (ETC) changes are triggered by oxidative stress [26]. Indeed, the highest prevalence of mtDNA deletions is reported in those skeletal muscle fibers exposed to oxidative injury [27][28]. Increased mtDNA deletions are related to modifications of mitochondrial enzymes in old primates and humans [29][30]. 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 [30][31]. 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 [32]. Dysfunctional mitochondria were also reported in spinal motor neurons from old humans, contributing to the denervation and collapse of skeletal muscle quality [33]. Notably, the denervation of skeletal muscle fibers triggers mitochondrial reactive species even in nearby innervated fibers, indicating a collateral mechanism in sarcopenia [34].
    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 [19][35]. Training exercises may reduce the mitochondrial release of proapoptotic proteins and the resultant DNA fragmentation [36][37]. Mitochondrial dysfunction may also induce a caspase-independent apoptotic pathway that contributes to the disruption of muscle quality in aging [38]. The calcium retention capacity was shown to be reduced in skeletal muscle mitochondria from old men, indicating mPTP sensitization to apoptosis [35]. 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 [39][40].

    2.3. 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 [41]. Nevertheless, an age-dependent decrease in mitochondrial biogenesis may be sustained by the defective response of PGC-1α to exercise [42]. 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 [4][7][16]. 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 [43][44][45].
    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 [46][47][48]. PGC-1α overexpression in skeletal muscle inhibits mitophagy, which appears enhanced in aging [46]. Genes related to mitophagy were described as downregulated in a cross-sectional study on physically inactive frail old women [49]. On the contrary, mitophagy and its regulatory proteins were increased in rodent models of sarcopenia [50][51]. Another study indicated that lysosomal dysfunction may cause an accumulation of disrupted mitochondria in the skeletal muscle of old mice [52].

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

    3.1. Mitochondria-Targeted Delivery Systems

    Mitochondrial delivery strategies can be classified either as referring to the molecular size and type or considering the molecular mechanism [53][54]. 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 [55][56][57]. 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 [58].

    3.1.1. 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 [58]. DLCs are conjugated to deliver antioxidant compounds, to selectively transport DNA or anticancer agents, sorbitol, metals, and copolymers [58]. 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 [59]. 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 [60]. Liposomes are spherical compounds consisting of phosphatidylglycerol, phosphatidylcholine, and cholesterol, with a hydrophilic core surrounded by a lipid bilayer [61]. Liposomes are nontoxic and can deliver large-sized drugs, including antioxidants, mitochondria-targeted molecules, or even mtDNA [62][63].

    3.1.2. 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 [64][65].
    Mitochondria signal peptides (MSPs) or mitochondria-targeting sequences (MTSs) are normally used to import proteins synthetized in ribosomes within mitochondria [66]. 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 [66].
    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 [67]. Indeed, compounds covalently conjugated to MMPs are able to mostly accumulate in mitochondria rather than the cytoplasm or nucleus [68].

    3.2. 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 [69][70][71]. 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 [72]. The 5-polyamidoamine dendrimer (G5-PAMAM) modified with ASSLNIA may synergistically improve skeletal muscle gene delivery [73]. The 12-mer peptide M12, which increases the binding affinity to myoblasts, conjugated with phosphorodiamidate morpholino oligomers may improve muscle function [74].
    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 [75]. The nicotinic acid derivative acipimox, an NAD+ precursor, is able to directly enhance skeletal muscle mitochondrial function in humans [76].
    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 [77]. 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 [78][79]. The mitochondria-targeted Szeto–Schiller peptide SS-31 was shown to improve exercise tolerance by increasing mitochondrial quality without mitochondrial content in aged mice [80].

    4. Conclusions

    Innovative pharmacology is able to produce molecules that can modulate mitochondria in several ways. However, 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.

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      Bellanti, F.; Buglio, A.L.; Vendemiale, G. Muscle Delivery of Mitochondria-Targeted Drugs for Sarcopenia. Encyclopedia. Available online: https://encyclopedia.pub/entry/37880 (accessed on 04 February 2023).
      Bellanti F, Buglio AL, Vendemiale G. Muscle Delivery of Mitochondria-Targeted Drugs for Sarcopenia. Encyclopedia. Available at: https://encyclopedia.pub/entry/37880. Accessed February 04, 2023.
      Bellanti, Francesco, Aurelio Lo Buglio, Gianluigi Vendemiale. "Muscle Delivery of Mitochondria-Targeted Drugs for Sarcopenia," Encyclopedia, https://encyclopedia.pub/entry/37880 (accessed February 04, 2023).
      Bellanti, F., Buglio, A.L., & Vendemiale, G. (2022, December 02). Muscle Delivery of Mitochondria-Targeted Drugs for Sarcopenia. In Encyclopedia. https://encyclopedia.pub/entry/37880
      Bellanti, Francesco, et al. ''Muscle Delivery of Mitochondria-Targeted Drugs for Sarcopenia.'' Encyclopedia. Web. 02 December, 2022.
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