Sarcopenia Pathophysiology: History
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Choon Young Kim

The pathophysiology of sarcopenia has multifactorial causes. Some cellular and molecular mechanisms have been suggested to be involved that include protein homeostasis imbalance, inflammation, mitochondrial dysfunction, and satellite cell dysfunction. These factors do not independently cause sarcopenia but interact with each other to cause sarcopenia.

  • sarcopenia
  • muscle
  • aging

1. Protein Homeostasis Imbalance

The balance between protein synthesis and breakdown, also known as protein homeostasis, contributes to the maintenance of mass in skeletal muscle, the largest reservoir of amino acids in the body. Aging induces a negative balance between protein synthesis and degradation. Specifically, a reduction in protein synthesis was reported with advancing age. The rate of synthesis of mixed muscle proteins including myofibrillar, mitochondrial, and sarcoplasmic proteins was reduced by 30% with advancing age. Additionally, the synthesis rate of myosin heavy chain (MHC), the contractile protein, was reduced in older people (~77 years of age) [1]. Moreover, mitochondrial protein synthesis decreases with age. In a post-absorptive human study, older men (75 years of age) showed lower postprandial muscle protein synthesis rates than young men (22 years of age) by 16% [2]. Besides changes in muscle protein synthesis, age-related alteration in protein degradation have also been reported [3].
Protein synthesis and protein degradation are regulated by different pathways. A major regulatory signaling pathway for protein synthesis involves insulin-like growth factor-1 (IGF-1)—phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt)—the mammalian target of rapamycin (mTOR) complex 1 axis [4]. IGF-1 stimulates muscle cells to activate downstream targets, which are required for protein synthesis [5]. This hormone interacts with its tyrosine kinase receptor to phosphorylate insulin receptor substrate (IRS)-1 and activates PI3K/Akt signaling [4]. Thereafter, phosphorylated Akt activates mTOR, resulting in phosphorylation of ribosomal protein S6 kinase (p70S6K) and the 4E-binding protein 1 (4E-BP1), which promotes protein synthesis by activating ribosomal protein S6 and releasing eukaryotic translation initiation factor eIF-4E, respectively. The level of IGF-1, the main anabolic signal in skeletal muscle, decreases with age [6]. Therefore, muscle protein synthesis declines with age.
Major regulating pathways for protein degradation in the muscle are the ubiquitin–proteasome system (UPS) and autophagy–lysosome system. The UPS rapidly eliminates misfolded proteins and short-lived regulatory proteins by labeling them with ubiquitin and transmitting them to the proteasome where proteins are degraded. The proteolytic component in the pathway is the 26S proteasome, composed of proteolytic 20S core particles capped by one or two 19S regulatory particles [7]. In this pathway, proteins fated to be degraded are linked to a chain of ubiquitin molecules by a cascade of ubiquitin ligases (E1, E2, and E3). Major muscle-specific E3 ubiquitin ligases are muscle atrophy F-box (MAFbx/atrogin-1) and muscle RING-finger 1 (MuRF1) [8]. After ubiquitin molecules attach to proteins by atrogin-1 and MuRF1, the polyubiquitin-tagged proteins are fragmented into peptides and amino acids by the 26S proteasome. The autophagy–lysosomal system, the other degradation machinery, is complementary to UPS-mediated degradation. An internal acidic pH environment coupled with different hydrolases and proteases in lysosomes enables efficient degradation of misfolded and aggregated proteins not degradable by the UPS [9]. Among the three types of autophagy in mammalian cells, namely, chaperone-mediated autophagy, microautophagy, and macroautophagy, macroautophagy plays a major role in muscle protein degradation [3]. Macroautophagy is responsible for removing entire regions of the cytosol such as dysfunctional organelles and protein aggregates by the formation of a double membraned vesicle called a phagosome followed by its fusion with lysosomes where the cargo is normally degraded. The elongation and expansion of the double membrane is due to two ubiquitin-like proteins, autophagy-related 12 (Atg12) and LC3, a human homolog of yeast Atg8. Atg12 is conjugated to Atg5, mediated by Atg7 and Atg10, and then interacts with Atg16 in a non-covalent manner. Non-lipidemic LC3-I is converted to lipidemic LC3-II, which is an autophagosomal marker whose upregulated levels indicate upregulation of autophagy, which integrates into the autophagosomal membrane. Additionally, the accumulation of p62, a receptor for cargo destined to be degraded by autophagy is considered a sign of impaired autophagy [10]. In skeletal muscles, the forkhead box O3 (FoxO3) is the main controller of the transcription of autophagy-related genes, including Bnip3 and Beclin1, as well as the aforementioned LC3, Atg4, Atg8, and Atg12 [11].
Several signaling pathways are interconnected in protein homeostasis. PI3K/Akt, induced by IGF-1 and enhances protein synthesis can also prevent protein degradation by phosphorylating and inactivating the FoxO transcription factor. The inactivated FoxO, which fails to translocate to the nucleus, prevents the upregulation of UPS genes including MuRF-1 and atrogin-1 in the skeletal muscle [12]. Myostatin, an autocrine and paracrine hormone produced by muscle cells, known to be a negative regulator of muscle mass, is also related to the degradation pathway. After myostatin binds to the activin type two receptor, downstream effector Smad2/3 is phosphorylated and activated. This phosphorylated Smad2/3 inhibits phosphorylation and activation of Akt leading to the reduction of FoxO phosphorylation. Unphosphorylated and, thereby, activated FoxO, as well as phosphorylated Smad2/3 can induce MuRF-1 and atrogin-1 expression, thereby inducing protein degradation [13]. In contrast, the inhibited Akt/mTOR pathway in response to myostatin also suppresses protein synthesis [14].
Several physiological changes during the aging process such as hormonal alteration and systemic inflammation have been demonstrated to affect either protein synthesis or protein degradation [15][16]. IGF-1 level was lower in the sarcopenic group than that in the non-sarcopenic group (98.53  ±  28.45 vs. 136.41  ±  48.95 ng/mL) in a cross-sectional study of more than 3000 subjects [17], which can impact protein homeostasis. The age-related decline of IGF-1 level, resulting from reduced liver IGF-1 production and the ability of skeletal muscle cells to produce IGF-1 locally is linked to protein synthesis reduction in older adults [18]. In addition, the salivary level of glucocorticoids, released from the adrenal cortex, which becomes dysfunctional in aging, increased in older adults with sarcopenia than in those without sarcopenia [19]. The increased levels of glucocorticoids inhibit protein synthesis and stimulate proteolysis in the skeletal muscle. Furthermore, increased expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), play a role as a mediator for stimulating muscle atrophy signaling [16].

2. Age-Related Chronic Low-Grade Inflammation

The increase in inflammation during the aging process, also known as inflammaging, has been suggested as one of the significant contributors to sarcopenia [20][21]. Inflammaging is characterized as low-grade, chronic, and systemic inflammation without infection. This low-grade and chronic inflammation makes it possible to differentiate sarcopenia from cachexia, which is related to cancer-related inflammation-induced muscle wasting. Inflammaging is a consequence of immunosenescence and cellular senescence [22]. Immunosenescence, the decline in immune function induced by aging, is characterized by thymic atrophy, accumulation of senescent T-cells, and impaired innate immunity in natural killer cells, macrophages, and neutrophils [23]. The senescent cells, which are in a permanent state of cell cycle arrest are nonproliferating cells but they display a senescence-associated secretory phenotype (SASP). The SASP releases proinflammatory cytokines, including TNF-α, interleukin-6 (IL-6), and C-reactive protein (CRP), which are known to be involved in the pathophysiology of age-related sarcopenia.
TNF-α, a proinflammatory cytokine whose levels are elevated in aged subjects, has been demonstrated to be involved in the progression of sarcopenia [24]. In a Chinese cohort study, high levels of TNF-α (>11.15 pg/mL) were associated with a 7.6-fold increased risk of sarcopenia [25]. A strong association between decline in grip strength and the TNF-α level was also demonstrated in a five-year study of change in thigh muscle area of 2177 participants aged 70–79 years [26]. Interestingly, pharmacological TNF-α blockade in 16–28-month-old mice prevented muscle atrophy and loss of type II fibers, accompanied by overall muscle function improvement [27]. IL-6, a proinflammatory cytokine secreted by many cells including monocytes and T lymphocytes is also associated with sarcopenia [24]. In a cross-sectional study of healthy older individuals, higher plasma levels of IL-6 and TNF-α were associated with lower muscle mass and lower muscle strength [28]. Additionally, significantly increased IL-6 (49.77 in sarcopenia vs. 39.72 pg/mL in control) levels have been reported in another cross-sectional study of 441 patients over >60 years of age [29]. The age-related increases in circulating IL-6 levels and their significant contribution to declines in skeletal muscle strength, quality, and function were also demonstrated in a randomized controlled clinical trial (RCT) with 99 mobility-limited older adults [30]. In addition, CRP produced by the liver has been reported to be significantly increased in the sarcopenia group compared to the control group based on a meta-analysis from 17 cross-sectional studies [20]. High CRP (>6.1 μg/mL) and IL-6 (>5 μg/mL) levels were associated with a two- to three-fold greater risk of losing muscle strength in a longitudinal three-year follow-up study conducted with 986 subjects with a mean age of 75 years [31].
The nuclear factor-kappa B (NF-κB) is the main regulator of inflammatory cytokine-mediated muscle atrophy. NF-κB comprises the subunits such as Rel/p65, c-Rel, and RelB which possess transactivation domains [32]. In an inactive state, NF-κB resides in the cytosol, tightly bound to the inhibitory protein IκB. In response to proinflammatory cytokine TNF-α, IκB kinase phosphorylates IκB and initiates IκB degradation via the ubiquitin–proteasome pathway, leaving NF-κB free and active; NF-κB then translocates to the nucleus and binds to promoter sequences at the κB domain [33]. Increased NF-κB signaling enhances inflammation by upregulating cytokine release and increases protein degradation by the UPS with upregulation of MuRF1 and atrogin-1 expression.
Meanwhile, the aging of skeletal muscle is possibly associated with increased nitration, a maker for oxidative stress, which can be increased with an inflammatory status [34][35]. The muscle is known to be vulnerable to oxidative stress and a key enzyme is the sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase (SERCA) [36]. Modification of nitration in aged muscle is increased by three-fold with a 40% loss in SERCA activity. Therefore, based on the fact that the physiological role of SERCA is to mediate muscle relaxation, inhibition of SERCA by nitration is likely to explain the muscle relaxation disorder observed in older subjects [37]. Moreover, a human study showed that high circulatory markers of inflammation are associated with peripheral muscle fatigue manifested by slower muscle contraction and relaxation in hospitalized geriatric patients [38].

3. Mitochondrial Dysfunction

A genomic and proteomic profiling study showed that genes involved in mitochondrial energy metabolism pathway were downregulated in aged rats and a significant correlation between gene expression and sarcopenia was observed [39]. Decreased expression of genes encoding subunits of the mitochondrial electron transport chain was also reported in human aged muscle samples [40]. Thus, mitochondrial dysfunction is suggested as a pathophysiology of sarcopenia. Impaired mitochondrial biogenesis and mitochondrial dynamics have been proposed to cause mitochondrial dysfunction in sarcopenic muscles [41].

3.1. Reduction of Mitochondrial Biogenesis

Mitochondrial biogenesis is a process that generates new mitochondria, with an increase in the number and density of mitochondria. In the muscle, which has a high metabolic rate, mitochondrial biogenesis is particularly important for producing ATP, which can facilitate muscle contraction and impact physical performance [42].
The process of mitochondrial biogenesis engages coordination between mitochondrial and nuclear genomes because mitochondrial proteins are encoded by nuclear and mitochondrial genomes. Although most of the proteins involved in mitochondrial genesis are encoded by the nuclear genome, a small number of crucial subunits of the electron transport chain complexes are encoded by mitochondrial DNA (mtDNA) [43]. In mtDNA transcription and translation, proliferator-activated receptor γ coactivator-1 alpha (Pgc-1α) is the master regulator of mitochondrial biogenesis. The Pgc-1α activation by either phosphorylation or deacetylation initiates the mitochondrial biogenesis, followed by stimulation of a series of nuclear transcription factors, such as nuclear respiratory factor-1 (Nrf-1), Nrf-2, and estrogen-related receptor alpha (ERRα). Once activated, Nrf-1/2 cofactors increase the expression of mitochondrial transcription factor A (Tfam), the final effect of mtDNA transcription and replication [44]. For proteins encoded by nuclear DNA (nDNA), all steps including transcription, translation, and preprotein synthesis occur in the cytoplasm. Translocase TIM23 is involved in directing the signal of preproteins toward the mitochondrial matrix. The nDNA as well as mtDNA encode proteins, thereby increasing mitochondrial biogenesis [44].
A decrease in mitochondrial biogenesis in aging as well as in sarcopenia have been reported in human as well as in vivo studies. Compared to those in young participants (22–24 years old), 50% of expression levels of key metabolic regulators of mitochondrial biogenesis, including sirtuin 3 (Sirt3) and Pgc-1α in the skeletal muscle of aged subjects (75–81 years old) was observed [45]. Moreover, individuals with sarcopenia exhibited reduced expression levels of Pgc-1α, ERRα, and other coactivators, such as Nrf-1 and Nrf-2, compared with those in individuals without sarcopenia [46]. In senescence-accelerated mouse prone-8 (SAMP8) mice, a well-studied murine model for age-related disease exhibiting typical features of skeletal muscle senescence, downregulation of Pgc-1α, Nrf-1, and Tfam during the onset and development of sarcopenia was observed [47].

3.2. Dysregulation of Mitochondrial Dynamics

Mitochondrial function is regulated by mitochondrial dynamics, and the processes are composed of the fusion and fission of mitochondria [48]. Due to mixed contents in the mitochondria via fusion and fission, a homogenous and healthy mitochondrial population can be maintained. By mitochondrial fusion, damaged mitochondria are fused into healthy mitochondria, resulting in the complementation of damaged features. Meanwhile, damaged parts from healthy mitochondria can be isolated and discarded via mitophagy [49]. Mitochondrial functions such as mtDNA stability, respiratory capacity, and mitophagy are linked to normal mitochondrial dynamics [48].
Mitochondrial proteins involved in fusion and fission are well characterized. Mitochondrial fusion is a two-step process including outer mitochondrial membrane (OMM) fusion and inner mitochondrial membrane (IMM) fusion. Several GTPase proteins mediate the fusion process. They are mitofusin 1 (Mfn1) and Mfn2 for OMM fusion, and optic atrophy-1 (Opa1) for IMM fusion. In mitochondrial fission, dynamin-related protein 1 (Drp1) binds to mitochondrial outer membrane proteins, which are four Drp1 receptors. They are fission 1 homolog protein (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics protein of 49 kDa (Mid49), and mitochondrial dynamic protein of 51 kDa/mitochondrial elongation factor1 (Mid51/Mief1). This recruitment of Drp1 from the cytosol to mitochondria is required for the mitochondrial fission process [49].
Previous studies have reported that mitochondrial dynamics are dysregulated in the skeletal muscle of individuals with sarcopenia. Mediators involved in mitochondrial dynamics are decreased or deficient in aged muscles. For instance, aged (35-month-old) rats possessed smaller mitochondria and exhibited increased levels of fission proteins including Drp1 and Fis1, by approximately two–three folds compared to young (5-month-old) rats [50]. In a human biopsy study, the protein expression levels of mitochondrial fusion factor Mfn2 were revealed to be significantly reduced in older individuals with sarcopenia than those in control individuals [51].

4. Satellite Cell Dysfunction

Satellite cells (SCs), skeletal muscle stem cells, regenerate repeatedly throughout life and preserve skeletal muscle integrity contributing to muscle mass and muscle regeneration after injury. Thus, SC dysfunction has been suggested to be closely related to the onset and progression of sarcopenia [52][53].
SCs are normally quiescent and are present peripheral to the myofiber and underneath the basal lamina. Upon injury, such as muscle damage or trauma, SCs are driven out of their quiescent state, become activated, and regenerate muscle. The regeneration of muscle consists of several steps. The committed SCs are activated, enter the cell cycle, and then proliferate and turn into myoblasts, which are then differentiated into myocytes. The myocytes are fused and form myotubes, which finally turn into mature myofiber, the basic unit of skeletal muscle [54][55]. Although this proportion of activated SCs replenish myofibers, other SCs self-renew and return to their niche to maintain a normal number of SCs.
Several transcription factors are involved in the precise regulation of SC quiescence and activation; therefore, each transcription factor can be used as a marker for detecting the SC process. Paired box 7 (Pax7) is known as a canonical marker of SC. Quiescent SC expresses high levels of Pax7 but not myogenic regulating factors (MRFs). When activated, SCs lose expression of Pax7 and express MRFs. In each step of myogenesis, different types of MRF expressions occur. When SCs turn into myoblasts, myogenic differentiation 1 protein (MyoD) and myogenic factor 5 (Myf5) are expressed. Subsequently, when myoblasts are differentiated into myocytes, both myogenin and muscle-specific regulatory factor 4 (Mrf4) are expressed. In the final mature myofiber, MHC is expressed [55].
Aging induces a decline in the regenerative capacity of SCs through numerical and functional changes. A significantly reduced number of SCs, particularly in type II muscle fibers of the elderly (70–86 years of age) compared to that of younger adults (18–40 years of age) has been reported [56]. The functional loss of SCs in aging has been reported to result in cell-autonomous loss in self-renewal [57], a conversion from the myogenic lineage into the fibrogenic lineage [58], and the loss of quiescence [59]. Moreover, SC-dependent declines in muscle regenerative capacity in aging can affect sarcopenia [60]. For example, depletion of SCs accelerates age-related degeneration of neuromuscular junctions, a synapse located between motor neurons and skeletal muscle, and is one of the manifestations of sarcopenia [61].

This entry is adapted from the peer-reviewed paper 10.3390/nu15112625

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