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Basic Research The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4
Min-Ji Kim1orcid, Ibotombi Singh Sinam2, Zerwa Siddique3,4, Jae-Han Jeon1, In-Kyu Lee5orcid
Diabetes & Metabolism Journal 2023;47(2):153-163.
Published online: January 12, 2023
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1Department of Internal Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea

2Bio-Medical Research Institute, Kyungpook National University Hospital, Daegu, Korea

3Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Korea

4BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, Korea

5Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea

Corresponding author: In-Kyu Lee orcid Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, 130 Dongdeok-ro, Jung-gu, Daegu 41944, Korea E-mail:
• Received: August 31, 2022   • Accepted: November 13, 2022

Copyright © 2023 Korean Diabetes Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • Sarcopenia, defined as a progressive loss of muscle mass and function, is typified by mitochondrial dysfunction and loss of mitochondrial resilience. Sarcopenia is associated not only with aging, but also with various metabolic diseases characterized by mitochondrial dyshomeostasis. Pyruvate dehydrogenase kinases (PDKs) are mitochondrial enzymes that inhibit the pyruvate dehydrogenase complex, which controls pyruvate entry into the tricarboxylic acid cycle and the subsequent adenosine triphosphate production required for normal cellular activities. PDK4 is upregulated in mitochondrial dysfunction-related metabolic diseases, especially pathologic muscle conditions associated with enhanced muscle proteolysis and aberrant myogenesis. Increases in PDK4 are associated with perturbation of mitochondria-associated membranes and mitochondrial quality control, which are emerging as a central mechanism in the pathogenesis of metabolic disease-associated muscle atrophy. Here, we review how mitochondrial dysfunction affects sarcopenia, focusing on the role of PDK4 in mitochondrial homeostasis. We discuss the molecular mechanisms underlying the effects of PDK4 on mitochondrial dysfunction in sarcopenia and show that targeting mitochondria could be a therapeutic target for treating sarcopenia.
Sarcopenia is defined as a progressive and generalized skeletal muscle disorder involving the accelerated loss of muscle mass and function. Sarcopenia can result from multiple pathologies; these include aging-associated reductions in muscle mass, cachexia caused by malignant tumors, muscle wasting resulting from acute diseases, and a decrease in muscle mass due to hereditary myopathy [1]. Sarcopenia is associated with adverse outcomes including falls, functional decline, frailty, reduced mobility, diminished quality of life, and fall-related injuries such as fractures, which can require costly hospitalization and extended rehabilitation, and may increase mortality.
The most widely cited definition of sarcopenia is from the European Working Group on Sarcopenia in Older People; based on this definition, large-scale studies suggest the prevalence of sarcopenia is 6% to 15% of the general population. Emerging evidence demonstrates that the incidence of sarcopenia increases with age: for example, one study showed an incidence of 1.6% in people aged 40 to 79 years and 3.6% in those aged >85 years using the European Working Group on Sarcopenia in Older People definition. Sarcopenia is associated not only with aging, but also with various metabolic diseases, including type 2 diabetes mellitus (T2DM), fatty liver/steatohepatitis, degenerative cranial nerve disease, and inflammatory disease [2]. The key etiology of increased sarcopenia in patients with metabolic diseases is decreased mitochondrial function. In support of other studies showing that mitochondrial dysfunction is the major cause of sarcopenia [3,4], in 2019, a key factor in cancer-induced sarcopenia was identified in the regulation of mitochondrial function (Fig. 1) [5].
Mitochondria are the powerhouse of cells and are vital in maintaining muscle mass and activity [6]. Among muscle cell types, a myofiber is a postmitotic, highly differentiated cell containing mitochondria as the sole provider of energy for movement and metabolism [7]. Interestingly, the function of muscle mitochondria depends on its locality and biochemical specializations: while intermyofibrillar mitochondria are involved in oxidative phosphorylation and modulation of Ca2+ flux, subsarcolemmal mitochondria control gene expression, and reactive oxygen species (ROS) levels [8,9]. To meet the high energy demands of skeletal muscle, mitochondria rely on dynamic regulation of quality control processes, which include mitochondrial oxidant-scavenging systems, mtDNA maintenance, calcium homeostasis, protein degradation and repair, mitodynamics, and autophagy pathways. Failure to maintain these processes, as in denervation or aging, results in muscle dysfunction, making mitochondrial impairment the hallmark of various myopathies [10].
Pyruvate dehydrogenase kinases (PDKs) are a family of mitochondrial enzymes that act to suppress the conversion of pyruvate to acetyl coenzyme A via inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC) [11]. In mammals, there are four isoenzymes of PDK (PDK1, 2, 3, and 4), which are expressed in a tissue-specific manner [12]. Among all PDKs, PDK4 is one of the most well-studied because its expression is dramatically changed in different physiological conditions [13,14]. Prolonged upregulation of PDK4 is also found in mitochondrial dysfunction-related metabolic diseases, especially pathologic muscle conditions associated with metabolic disease [15]. Here, we discuss the molecular mechanisms and effects of mitochondrial dysfunction in sarcopenia, and specifically the role of PDK4 activity, and show that targeting mitochondria could be a therapeutic target for treating sarcopenia.
Optimal mitochondrial activity depends on metabolic flexibility between processes catalyzed by various enzymes, especially the PDC, which controls pyruvate entry into the tricarboxylic acid cycle and thus the provision of adenosine triphosphate (ATP) for normal cellular activities. PDC activity is controlled by mitochondrial PDKs; among these, PDK4 is highly expressed in both starved and obese muscle tissue in animal models [16]. PDK4 regulates activity of the complex by inhibitory phosphorylation, which reduces carbon influx and, consequently, the onset of mitochondrial-mediated direct and indirect muscle pathologies. These can include muscle atrophy, sarcopenia, cancer cachexia, obesity-induced muscle insulin resistance, diabetes, and aging [5,17-20]. Moreover, PDK4 causes mitochondrial defects by interacting with proteins other than PDC, meaning the effect of PDK4 on mitochondria occurs via a range of both canonical and non-canonical pathways [21,22].
Mitochondrial energetics and PDK4 in muscle
Skeletal muscle activity relies on dynamic mitochondrial ATP production that responds to that variation in metabolic rate between rest and work. Consequently, elevations in mitochondrial ROS become a normal part of muscle physiology [23]. However, altered mitochondrial energetics and other cellular stressors can cause abnormal elevations in ROS levels. In turn, this exacerbates mitochondrial dysfunction via enhanced proteolytic degradation (autophagy); impaired mammalian target of rapamycin activity, which is required for protein synthesis; reduced ATP levels; and enhanced fission. As a result, mitochondrial dysfunction is associated with myopathies such as sarcopenia, muscle atrophy, amyotrophic lateral sclerosis, cancer cachexia, diabetes, and aging [24,25].
PDK4 activity can both affect and be affected by ROS generation. For example, oxidative skeletal muscle from genetically obese and diabetic mice shows forkhead box protein O1 (FOXO1) and peroxisome proliferator-activated receptor (PPAR)α/δ-mediated increases in PDK4 levels. This results in a metabolic shift from glucose to fatty acid oxidation, and a subsequent reduction in oxidative phosphorylation activity and increase in proton leakage, which leads to higher mitochondrial ROS levels and susceptibility to insulin resistance [26]. In addition, administration of the FOXO1-selective inhibitor AS1842856 in diabetic rat hearts improved glucose oxidation, with a concomitant decrease in PDK4 and carnitine palmitoyltransferase 1 expression, thus reducing ROS levels and improving muscle growth, suggesting that PDK4 may mediate the associations between mitochondrial dysfunction and muscle wasting (Fig. 2) [27].
PDK4 and mitochondrial turnover in muscle
Mitochondrial surveillance is crucial for proper functioning and is done by specific proteases through selective removal of damaged mitochondria. Lon peptidase 1 (LONP1) is an important protease that resides in the mitochondrial matrix and is involved in muscle mitochondrial quality control. A recent study showed skeletal muscle-specific ablation of LONP1 (LONP1 mKO) resulted in impaired mitochondrial protein turnover and increased autophagy upon muscle disuse, worsening muscle loss [28]. Inactivity-induced muscle atrophy results in lower ATP output and an increase in adenosine monophosphate (AMP); this energy imbalance activates AMP-activated protein kinase, an energy sensor. In turn, this activates FOXO3, thereby increasing expression of atrogenes involved in both the ubiquitin-proteasome system and autophagy, leading to proteolysis (Fig. 2) [29]. Interestingly, in LONP1 mKO mice, comparative analysis of MitoCarta2.0 and mass spectrometry proteomics of LONP1 mKO-isolated mitochondria showed upregulation of various mitochondrial matrix proteins, including PDK4 [28]. In cardiomyocytes, PDK4 is a direct substrate of LONP1, with PDK4 turnover via this pathway regulating PDC activity [30]. Taken together, these results suggest that the effect of LONP1 on mitochondrial turnover may be mediated by PDK4.
PDK4-mediated mitochondrial-associated membrane formation in muscle
Calcium (Ca2+) is essential for muscle contraction, since it maintains mitochondrial activity; specifically, Ca2+ stimulates pyruvate dehydrogenase phosphatase 1, which dephosphorylates and activates the PDC to promote glucose metabolism. Furthermore, Ca2+ stimulates tricarboxylic acid cycle enzymes and ATP synthase to enhance ATP synthesis [31]. Sarcoplasmic reticulum is a special form of endoplasmic reticulum (ER) in striated muscle that interacts with mitochondria to exchange phospholipids and Ca2+. This inter-organelle interaction is termed a mitochondrial-associated membrane (MAM) and modulates Ca2+ transfer via formation of a macromolecular complex consisting of inositol 1,4,5-trisphosphate receptor type 1, glucose-regulated protein 75, and voltage-dependent anion channel 1. MAM-related muscle impairment is implicated in muscle dystrophy, aging, and insulin resistance, where a reduction in MAM formation aggravates these disorders [22,32].
PDK4 was recently identified in the MAM fraction, where it interacts with and stabilizes the inositol 1,4,5-trisphosphate receptor type 1–glucose-regulated protein 75-voltage-dependent anion channel 1 complex in skeletal muscle. Under normal conditions, palmitate treatment causes mitochondrial Ca2+ overload and leads to elevated ROS levels, resulting in the opening of mitochondrial permeability transition pores, cytochrome c release, and apoptosis. Moreover, MAM impairment causes ER stress and activates c-Jun N-terminal kinase and Ser/Thr-phosphorylation of insulin receptor substrate 1, resulting in insulin resistance (Fig. 2) [22,33]. However, in high-fat diet-challenged Pdk4−/− mice, MAM-related mitochondrial Ca2+ uptake and activation of PDC were reduced, resulting in enhanced glucose oxidation and improved glucose tolerance and insulin sensitivity resistance [22,33]. PDK4 therefore appears to have a vital role in the effect of fatty acid availability on MAM dysfunction and consequent metabolic perturbations.
As mitochondria divide frequently, a dynamic balance between fusion and elongation is required to maintain structural and functional integrity. This is done by various proteins located inside and outside the mitochondria. Key proteins that promote mitochondrial fission include dynamin-related protein 1 (DRP1) and fission 1, whereas proteins regulating mitochondrial fusion include optic atrophy 1 and mitofusion 1 and 2 (MFN1/2). Increased mitochondrial fission during prolonged inactivity is associated with muscle atrophy, with the resultant mitochondria more fragmented/round, producing more ROS, and unable to generate ATP [34]. Muscle from patients with chronic kidney disease shows mitochondrial dysfunction, with increased PDK4-mediated PDC inactivation and distorted dynamics resulting from suppressed Mfn-1 expression and a low phospho-DRP1(S637)/DRP1 ratio [35]. Various adapters interact with DRP1; however, non-canonical regulation of mitochondrial dynamics by PDK4 was recently reported, which promoted Drp1-mediated fission under stress conditions via phosphorylation of Septin2 at Serine218. This further strengthens the evidence that PDK4 directly regulates enzymes involved in mitochondrial quality processes (Fig. 2) [36].
Mitochondrial fission precedes mitophagy, which is a quality control mechanism to remove dysfunctional mitochondria as a whole or cause budding off as mitochondrial-derived vesicles. Mitophagy occurs through both ubiquitin-dependent (i.e., PTEN-induced kinase 1 [PINK1]-PARKIN) and ubiquitin-independent (e.g., BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 [BNIP3]/BNIP3L, FUN14 domain containing 1 [FUNDC1], BCL213) pathways [37]. Loss of mitochondrial membrane potential activates mitophagy and causes lysosome-associated mitochondrial degradation. Impaired mitophagy is evident in skeletal muscle during aging and sarcopenia. A cross-sectional study reported that inactive older women show significantly lower gene expression (approximately 30% to 40%) of DRP1, BNIP3, BECLIN1, autophagy related 7 (ATG7), and PARKIN in muscle [38]. Muscle-specific ablation of PARKIN in mice results in lower mitophagy flux in response to acute exercise and training; by contrast, overexpression of PARKIN in older mice inhibits mitochondrial permeability transition pore opening, thus improving muscle strength by increasing mitochondrial content [39]. A recent study showed that Mfn2 deficiency-related sarcopenia in aged muscle activates hypoxia inducible factor 1 subunit alpha (HIF1α)-BNIP3, which appears to be an adaptive mitophagy strategy to compensate for muscle loss. PDK4 is a target gene of HIF1α, and muscle from old control and young and old Mfn2-knockout mice showed increased Pdk4 mRNA levels but not Pdk1 levels [40]. In addition, PDK4 stimulates mitophagy via PINK-PARKIN stabilization by elevating pyruvate [41]. Overall, although there is some evidence that PDK4 regulates mitophagy, further studies are required.
PDK4 is expressed in all skeletal muscle types (fast-twitch glycolytic, fast-twitch oxidative, and slow-twitch oxidative), with its expression further induced by fasting [42]. The mechanism responsible for the regulation of PDK4 gene expression has been extensively studied. The transcription factors FOXO1 [43], PPARα [44], PPARδ, estrogen-related receptor-α, and transcriptional co-activator PPARγ co-activator-1 [45] are the primary regulators proposed to upregulate PDK4. In the fed condition, increased serum insulin levels activate protein kinase B, also known as AKT, leading to suppression of FOXO1-mediated PDK4 expression, whereas during starvation, a decline in insulin levels reactivates FOXO1 and enhances PDK4 expression [46]. In healthy states, this dynamic change in PDK4 levels is critical for the metabolic switch from glucose to fatty acid oxidation [11,47], which is facilitated by PDK4 having a very short half-life (approximately 1 hour) relative to other mitochondrial proteins due to its rapid degradation by the mitochondrial Lon protease [30].
There is convincing evidence that PDK4 is closely related to metabolic dysfunction and muscular atrophy. In genetically obese, diet-induced obese, and insulin-resistant mice, as well as in diabetic rats, PDK4 expression is consistently elevated in skeletal muscle, while expression of the other PDKs remain unchanged [16,22,48]. Furthermore, loss of the fatty acid translocase cluster of differentiation 36 dampens starvation-induced FOXO1 and PDK4 expression [26], suggesting that fatty acid uptake stimulates PDK4 expression. Increased expression, coupled with enhanced stability by fatty acids, prolongs upregulation of PDK4 in insulin-resistant states [16]. Indeed, that PDK4 may have a causal role in insulin resistance is suggested by previous studies showing that genetic ablation of Pdk4 protects mice from high-fat diet-induced glucose intolerance and insulin resistance [49,50], although recent studies also suggest actions of PDK2 [51] and PDK4 [52-54] that are independent of PDC regulation.
Furthermore, increased PDK4 expression correlates with aging [40], atrophic muscle [5,25], and severe muscle loss in cancer cachexia [5], T2DM [46], glucocorticoids [55], sepsis [56], amyotrophic lateral sclerosis [25], and muscle disuse [28]. Treatment of C2C12 myotubes with culture medium collected from mouse colorectal cancer cells (C26) induces PDK4 expression and markedly reduces the size of C2C12 muscle fibers, while knockdown of PDK4 prevents tumor media-induced shrinkage of muscle fiber. Furthermore, overexpression of PDK4 induces mitochondrial dysfunction and muscle fiber shrinkage [5]. Together, these findings suggest that PDK4 plays a central role in mediating metabolic instability-induced skeletal muscle dysfunction (Fig. 3).
Aberrant activation of protein degradation is the primary pathway leading to muscle atrophy, with the ubiquitin-proteasome pathway serving a pivotal role in the mediation of protein degradation [57]. E3 ligases mediate protein ubiquitination; proteasomes then identify poly-ubiquitinated proteins and trigger degradation [58]. There are two muscle-specific E3 ligases: muscle RING finger 1 (MuRF1) and muscle atrophy F box (MAFbx) [59]. During muscle atrophy, MuRF1 and MAFbx are overexpressed: inhibiting the function of MuRF1 and MAFbx suppresses muscle loss, attenuating muscle atrophy [60,61]. A recent study [62] indicates that overexpression or dexamethasone (Dex)-mediated induction of PDK4 enhances interaction between myogenin (MYOG) and MAFbx, but not between MYOG and MuRF1, which suggests that PDK4 promotes MAFbx recruitment to catalyze muscle atrophy-induced MYOG degradation (Fig. 4); by contrast, Pdk4−/− mice exert resistance against glucocorticoid-induced muscle atrophy. In a Dex and cancer cachexia induced mouse model of atrophy, expression of PDK4 and MAFbx are upregulated, whereas knockdown of PDK4 reduces MAFbx expression [62]. Taken together, PDK4-dependent activation of the ubiquitin-proteasome pathway appears to underly the promotion of muscle atrophy by directly targeting the muscle-specific E3 ligase MAFbx.
In addition to enhanced muscle proteolysis, aberrant myogenesis is also a critical factor in muscle atrophy. Many pathological conditions such as obesity, T2DM, Cushing’s syndrome, long-term corticosteroid therapy, and cancer cachexia impair myogenesis [5,63-65]. Inactivation of myogenesis is also observed in diseases such as motor neuron degeneration, Duchenne muscular dystrophy, and spinal and bulbar muscular atrophy [66,67]. Muscle satellite cells are stem cells with self-renewal and differentiation potency, and when muscle disruption occurs, proliferative satellite cells can differentiate into myotubes and contribute to muscle regeneration [68], while defects in muscle regeneration result in muscle atrophy. Muscle regeneration is controlled by four highly related basic-helixloop-helix transcription factors known as the myogenic regulatory factors: myogenic factor 5, myoblast determination protein 1, myogenin, and myogenic regulatory factor 4/myogenic factor 6 [69].
PDK4 is implicated in the regulation of myogenesis and muscle atrophy (Fig. 4) [62]: PDK4 directly phosphorylates MYOG leading to MYOG ubiquitination and degradation. MYOG plays a crucial role in skeletal muscle differentiation and development by regulating expression of Mymk (myomaker, myoblast fusion factor), Mymx (myomixer, myoblast fusion factor), and myosin heavy chain, the key factors involved in the muscle differentiation and fusion process; as a result, suppressing PDK4 stabilizes MYOG and enhances muscle regeneration [62], while overexpression or induction of PDK4 by Dex decreases MYOG protein levels [62], suppressing myoblast differentiation and inhibiting myogenesis [5]. Thus, PDK4 has critical roles in regulating myogenic differentiation and muscle regeneration.
Mitochondria are the powerhouse of cells and serve vital functions to maintain muscle mass and activity. However, mitochondria are also actively involved in metabolic changes, which can occur via MAM formation, mitochondrial quality control, and myogenesis. Evidence suggests that mitochondrial dysfunction is observed in muscle atrophy associated with metabolic syndromes; therefore, targeting mitochondrial dysfunction could be a promising therapeutic strategy for treating sarcopenia. In this review, we have discussed the recent evidence and the potential mechanisms by which PDK4 may act in mitochondrial dysfunction in sarcopenia. In addition, we discussed non-canonical pathways of PDK4-mediated muscle atrophy, which occur independently of the PDC. Our group has shown that PDK4 has non-canonical roles in MAM formation [22] and mitochondrial quality control [36], suggesting further investigation is needed to uncover other mechanisms of PDK4 involvement in regulating mitophagy and myogenesis and their potential impact on metabolic disease-related sarcopenia.


No potential conflict of interest relevant to this article was reported.


This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No.2022R1C1C101089811), and supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR22C1832).

Fig. 1.
The association between risk factors of sarcopenia and mitochondrial dysfunction. Sarcopenia, generally defined as aging-related loss of muscle mass and function, is closely associated with other genetic or environmental factors. Sarcopenia pathogenesis occurs in multiple ways: genetic predisposition, aging, and disuse of muscle lead to transcriptional reprogramming or epigenetic modification; cancer cachexia or nutrient malabsorption cause low energy availability; metabolic diseases, such as type 2 diabetes mellitus (T2DM) and obesity, lead to metabolic disturbances; infection and sepsis cause inflammation; and steroids and other drugs can lead to catabolism and proteolysis. All these risk factors cause mitochondrial dysfunction, which results in sarcopenia via several mechanisms: defects in mitochondrial dynamics, such as fusion/fission; impaired mitochondrial quality control, including mitochondrial biogenesis; mitophagy and autophagy; dysfunctions in oxidative phosphorylation (OXPHOS), which is important in energy generation; and reactive oxygen species (ROS) production, which originates in dysregulated OXPHOS. Mechanistically, these factors decrease muscle strength and cause loss of muscle mass, which are associated with an increased risk of falls and fractures, functional decline, frailty, disability, and hospitalization with poorer health outcomes.
Fig. 2.
Muscle atrophy induces mitochondrial dysfunction through multiple pathways. Prolonged inactivity and other myopathies elevate reactive oxygen species (ROS) levels, which regulate different mitochondrial systems. Increased endoplasmic reticulum (ER) stress caused by calcium (Ca2+) overload and ROS results in Ca2+ influx into mitochondria through pyruvate dehydrogenase kinase 4 (PDK4)-mediated stabilization of inositol 1,4,5 trisphosphate receptor type 1 (IP3R1)–glucose-regulated protein 75 (GRP75)–voltage-dependent anion-selective channel 1 complex at the mitochondria-associated ER membrane. Increased mitochondrial Ca2+ content causes a drop in mitochondrial membrane potential (ΔΨm) leading to the opening of mitochondrial permeability transition pores (mPTP) to release cytochrome c, which activates apoptosis-inducing factor (AIF), leading to the onset of caspase 3-mediated cell death. Muscle atrophy causes increased fission via septin 2 (SEPT2)-mediated dynamin-related protein 1 (DRP1) upregulation. This imbalance between fusion and fission generates ROS and a lower ΔΨm, leading to dysfunctional mitochondrial-mediated autophagy (mitophagy). This occurs via suppressed PTEN-induced kinase 1 (PINK1)-PARKIN interaction, as well as reduced autophagic flux by lysosome adapter accumulation. Fission also causes a drop in ATP synthesis and impaired electron transport chain activity, leading to the activation of 5´ AMP-activated protein kinase (AMPK)–forkhead box protein O3 (FOXO3)-dependent atrogenes, which cause protein degradation (proteolysis). An increase in free-fatty acids (FFAs) caused by myopathologic metabolic alterations results in a switch from glucose oxidation to beta-oxidation. This causes an increase in FOXO1-PDK4 activity leading to the inactivation of the pyruvate dehydrogenase complex (PDC) by PDK4. Synergistically, FFAs also inhibit Lon peptidase 1 (LonP1), which degrades PDK4 in the mitochondria. Overall, this decreases oxidative phosphorylation (OXPHOS), leading to metabolic inflexibility-related myopathies. Acetyl-CoA, acetyl coenzyme A; ADP, adenosine diphosphate; BNIP3, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3; FIS1, mitochondrial fission 1 protein; FUNDC1, FUN14 domain containing 1; H+, proton ion; LC3B, microtubule-associated proteins 1A/1B light chain 3B; MFF, mitochondrial fission factor; NDP52, nuclear dot protein 52; OPTN, optineurin; P62, sequestosome 1 (SQSTM1); TCA, tricarboxylic acid cycle; TIM, translocase of the inner membrane; TOM, translocase of the outer membrane; Ub, ubiquitin.
Fig. 3.
Schematic of the involvement of pyruvate dehydrogenase kinase 4 (PDK4) in regulating muscle protein degradation and atrophic gene expression. In the pathological state, PDK4 is activated and can contribute to mitochondrial damage, as well as transcription of atrophy-related genes culminating in muscle atrophy. The transcription factor forkhead box protein O1 (FOXO1) is proposed to upregulate transcription of PDK4. During starvation, a decline in insulin levels activates FOXO1, which enhances PDK4 expression. PDK4 is highly expressed in cancer cachexia, type 2 diabetes mellitus (T2DM), glucocorticoid-induced myopathy, sepsis, amyotrophic lateral sclerosis (ALS), muscle disuse, and aging. Overexpression of PDK4 induces mitochondrial dysfunction and muscle protein degradation, giving PDK4 a central role in mediating metabolic instability-induced skeletal muscle dysfunction. Acetyl-CoA, acetyl coenzyme A; ATP, adenosine triphosphate; LonP1, Lon peptidase 1; MAFbx, muscle atrophy F-box; MuRF1, muscle RING finger 1; PDC, pyruvate dehydrogenase complex; PI3K, phosphatidylinositol-3-kinase; SC, satellite cell.
Fig. 4.
Pyruvate dehydrogenase kinase 4 (PDK4) and regulation of myogenesis. The ubiquitin-proteasome pathway serves a pivotal role in the mediation of protein degradation in muscle atrophy. In normal muscle, the transcription factor myogenin (MYOG) activates transcription of the myogenic genes MYMX (myomixer, myoblast fusion factor) and MYMK (myomaker, myoblast fusion factor). By contrast, during dexamethasone-induced muscle atrophy, induction of PDK4 leads to phosphorylation (P) of myogenin (MYOG) and recruitment of muscle atrophy F-box (MAFbx), which polyubiquitinates (Ub) MYOG, leading to its degradation and preventing transcription of myogenic genes. MyHC, myosin heavy chain; UPS, ubiquitin-proteasome system.
  • 1. Shimokata H, Shimada H, Satake S, Endo N, Shibasaki K, Ogawa S, et al. Chapter 2 Epidemiology of sarcopenia. Geriatr Gerontol Int 2018;18 Suppl 1:13-22.ArticlePubMedPDF
  • 2. Fu X, Zhu M, Zhang S, Foretz M, Viollet B, Du M. Obesity impairs skeletal muscle regeneration through inhibition of AMPK. Diabetes 2016;65:188-200.ArticlePubMedPMCPDF
  • 3. Liu X, Qu H, Zheng Y, Liao Q, Zhang L, Liao X, et al. Mitochondrial glycerol 3-phosphate dehydrogenase promotes skeletal muscle regeneration. EMBO Mol Med 2018;10:e9390.ArticlePubMedPMCPDF
  • 4. Hyatt H, Deminice R, Yoshihara T, Powers SK. Mitochondrial dysfunction induces muscle atrophy during prolonged inactivity: a review of the causes and effects. Arch Biochem Biophys 2019;662:49-60.ArticlePubMedPMC
  • 5. Pin F, Novinger LJ, Huot JR, Harris RA, Couch ME, O’Connell TM, et al. PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia. FASEB J 2019;33:7778-90.ArticlePubMedPMCPDF
  • 6. Abbatecola AM, Paolisso G, Fattoretti P, Evans WJ, Fiore V, Dicioccio L, et al. Discovering pathways of sarcopenia in older adults: a role for insulin resistance on mitochondria dysfunction. J Nutr Health Aging 2011;15:890-5.ArticlePubMedPDF
  • 7. Picca A, Calvani R, Bossola M, Allocca E, Menghi A, Pesce V, et al. Update on mitochondria and muscle aging: all wrong roads lead to sarcopenia. Biol Chem 2018;399:421-36.ArticlePubMed
  • 8. Barbieri E, Sestili P. Reactive oxygen species in skeletal muscle signaling. J Signal Transduct 2012;2012:982794.ArticlePubMedPMCPDF
  • 9. Boncompagni S, Rossi AE, Micaroni M, Beznoussenko GV, Polishchuk RS, Dirksen RT, et al. Mitochondria are linked to calcium stores in striated muscle by developmentally regulated tethering structures. Mol Biol Cell 2009;20:1058-67.ArticlePubMedPMC
  • 10. Twig G, Hyde B, Shirihai OS. Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta 2008;1777:1092-7.ArticlePubMedPMC
  • 11. Zhang S, Hulver MW, McMillan RP, Cline MA, Gilbert ER. The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility. Nutr Metab (Lond) 2014;11:10.ArticlePubMedPMCPDF
  • 12. Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J 1998;329(Pt 1):191-6.ArticlePubMedPMCPDF
  • 13. Roche TE, Hiromasa Y. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci 2007;64:830-49.ArticlePubMedPMCPDF
  • 14. Sugden MC, Holness MJ. Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases. Arch Physiol Biochem 2006;112:139-49.ArticlePubMed
  • 15. Park S, Jeon JH, Min BK, Ha CM, Thoudam T, Park BY, et al. Role of the pyruvate dehydrogenase complex in metabolic remodeling: differential pyruvate dehydrogenase complex functions in metabolism. Diabetes Metab J 2018;42:270-81.ArticlePubMedPMCPDF
  • 16. Holness MJ, Kraus A, Harris RA, Sugden MC. Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slowtwitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDK induced by high-fat feeding. Diabetes 2000;49:775-81.ArticlePubMedPDF
  • 17. Crossland H, Constantin-Teodosiu D, Greenhaff PL, Gardiner SM. Low-dose dexamethasone prevents endotoxaemia-induced muscle protein loss and impairment of carbohydrate oxidation in rat skeletal muscle. J Physiol 2010;588(Pt 8):1333-47.ArticlePubMedPMC
  • 18. Lee IK. The role of pyruvate dehydrogenase kinase in diabetes and obesity. Diabetes Metab J 2014;38:181-6.ArticlePubMedPMC
  • 19. Manickam R, Oh HY, Tan CK, Paramalingam E, Wahli W. Metronidazole causes skeletal muscle atrophy and modulates muscle chronometabolism. Int J Mol Sci 2018;19:2418.ArticlePubMedPMC
  • 20. Zhang L, Keung W, Samokhvalov V, Wang W, Lopaschuk GD. Role of fatty acid uptake and fatty acid beta-oxidation in mediating insulin resistance in heart and skeletal muscle. Biochim Biophys Acta 2010;1801:1-22.PubMed
  • 21. Jeon JH, Thoudam T, Choi EJ, Kim MJ, Harris RA, Lee IK. Loss of metabolic flexibility as a result of overexpression of pyruvate dehydrogenase kinases in muscle, liver and the immune system: therapeutic targets in metabolic diseases. J Diabetes Investig 2021;12:21-31.ArticlePubMedPMCPDF
  • 22. Thoudam T, Ha CM, Leem J, Chanda D, Park JS, Kim HJ, et al. PDK4 augments ER-mitochondria contact to dampen skeletal muscle insulin signaling during obesity. Diabetes 2019;68:571-86.ArticlePubMedPMCPDF
  • 23. Calvani R, Joseph AM, Adhihetty PJ, Miccheli A, Bossola M, Leeuwenburgh C, et al. Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy. Biol Chem 2013;394:393-414.ArticlePubMedPMC
  • 24. Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT, et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 2009;119:573-81.ArticlePubMedPMC
  • 25. Palamiuc L, Schlagowski A, Ngo ST, Vernay A, Dirrig-Grosch S, Henriques A, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med 2015;7:526-46.ArticlePubMedPMCPDF
  • 26. Nahle Z, Hsieh M, Pietka T, Coburn CT, Grimaldi PA, Zhang MQ, et al. CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPAR delta/beta-mediated adaptation to metabolic stress. J Biol Chem 2008;283:14317-26.PubMedPMC
  • 27. Yan D, Cai Y, Luo J, Liu J, Li X, Ying F, et al. FOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes. J Cell Mol Med 2020;24:7850-61.ArticlePubMedPMCPDF
  • 28. Xu Z, Fu T, Guo Q, Zhou D, Sun W, Zhou Z, et al. Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength. Nat Commun 2022;13:894.ArticlePubMedPMCPDF
  • 29. Sanchez AM, Csibi A, Raibon A, Cornille K, Gay S, Bernardi H, et al. AMPK promotes skeletal muscle autophagy through activation of forkhead FoxO3a and interaction with Ulk1. J Cell Biochem 2012;113:695-710.ArticlePubMed
  • 30. Crewe C, Schafer C, Lee I, Kinter M, Szweda LI. Regulation of pyruvate dehydrogenase kinase 4 in the heart through degradation by the lon protease in response to mitochondrial substrate availability. J Biol Chem 2017;292:305-12.ArticlePubMedPMC
  • 31. Rossi A, Pizzo P, Filadi R. Calcium, mitochondria and cell metabolism: a functional triangle in bioenergetics. Biochim Biophys Acta Mol Cell Res 2019;1866:1068-78.ArticlePubMed
  • 32. Pauly M, Angebault-Prouteau C, Dridi H, Notarnicola C, Scheuermann V, Lacampagne A, et al. ER stress disturbs SR/ ER-mitochondria Ca2+ transfer: implications in Duchenne muscular dystrophy. Biochim Biophys Acta Mol Basis Dis 2017;1863:2229-39.ArticlePubMed
  • 33. Arruda AP, Hotamisligil GS. Calcium homeostasis and organelle function in the pathogenesis of obesity and diabetes. Cell Metab 2015;22:381-97.ArticlePubMedPMC
  • 34. Romanello V, Guadagnin E, Gomes L, Roder I, Sandri C, Petersen Y, et al. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J 2010;29:1774-85.ArticlePubMedPMC
  • 35. Xu C, Kasimumali A, Guo X, Lu R, Xie K, Zhu M, et al. Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease. Nephrology (Carlton) 2020;25:230-8.ArticlePubMedPDF
  • 36. Thoudam T, Chanda D, Sinam IS, Kim BG, Kim MJ, Oh CJ, et al. Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status. Proc Natl Acad Sci U S A 2022;119:e2120157119.ArticlePubMedPMC
  • 37. Leduc-Gaudet JP, Hussain SN, Barreiro E, Gouspillou G. Mitochondrial dynamics and mitophagy in skeletal muscle health and aging. Int J Mol Sci 2021;22:8179.ArticlePubMedPMC
  • 38. Drummond MJ, Addison O, Brunker L, Hopkins PN, McClain DA, LaStayo PC, et al. 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;69:1040-8.ArticlePubMedPMC
  • 39. Chen CC, Erlich AT, Hood DA. Role of Parkin and endurance training on mitochondrial turnover in skeletal muscle. Skelet Muscle 2018;8:10.ArticlePubMedPMCPDF
  • 40. Sebastian D, Sorianello E, Segales J, Irazoki A, Ruiz-Bonilla V, Sala D, et al. Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway. EMBO J 2016;35:1677-93.ArticlePubMedPMCPDF
  • 41. Park S, Choi SG, Yoo SM, Nah J, Jeong E, Kim H, et al. Pyruvate stimulates mitophagy via PINK1 stabilization. Cell Signal 2015;27:1824-30.ArticlePubMed
  • 42. Peters SJ, Harris RA, Heigenhauser GJ, Spriet LL. Muscle fiber type comparison of PDH kinase activity and isoform expression in fed and fasted rats. Am J Physiol Regul Integr Comp Physiol 2001;280:R661-8.ArticlePubMed
  • 43. Furuyama T, Kitayama K, Yamashita H, Mori N. Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochem J 2003;375(Pt 2):365-71.ArticlePubMedPMCPDF
  • 44. Wu P, Peters JM, Harris RA. Adaptive increase in pyruvate dehydrogenase kinase 4 during starvation is mediated by peroxisome proliferator-activated receptor alpha. Biochem Biophys Res Commun 2001;287:391-6.PubMed
  • 45. Wende AR, Huss JM, Schaeffer PJ, Giguere V, Kelly DP. PGC1alpha coactivates PDK4 gene expression via the orphan nuclear receptor ERRalpha: a mechanism for transcriptional control of muscle glucose metabolism. Mol Cell Biol 2005;25:10684-94.PubMedPMCPDF
  • 46. Kim YI, Lee FN, Choi WS, Lee S, Youn JH. Insulin regulation of skeletal muscle PDK4 mRNA expression is impaired in acute insulin-resistant states. Diabetes 2006;55:2311-7.ArticlePubMedPDF
  • 47. Zhang D, Li Y, Yao X, Wang H, Zhao L, Jiang H, et al. miR-182 regulates metabolic homeostasis by modulating glucose utilization in muscle. Cell Rep 2016;16:757-68.ArticlePubMed
  • 48. Wu P, Inskeep K, Bowker-Kinley MM, Popov KM, Harris RA. Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes. Diabetes 1999;48:1593-9.ArticlePubMedPDF
  • 49. Hwang B, Jeoung NH, Harris RA. Pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) deficiency attenuates the longterm negative effects of a high-saturated fat diet. Biochem J 2009;423:243-52.ArticlePubMedPDF
  • 50. Jeoung NH, Harris RA. Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice. Am J Physiol Endocrinol Metab 2008;295:E46-54.ArticlePubMedPMC
  • 51. Shi G, McQuibban GA. The mitochondrial rhomboid protease PARL is regulated by PDK2 to integrate mitochondrial quality control and metabolism. Cell Rep 2017;18:1458-72.ArticlePubMed
  • 52. Lee SJ, Jeong JY, Oh CJ, Park S, Kim JY, Kim HJ, et al. Pyruvate dehydrogenase kinase 4 promotes vascular calcification via SMAD1/5/8 phosphorylation. Sci Rep 2015;5:16577.ArticlePubMedPMCPDF
  • 53. Liu Z, Chen X, Wang Y, Peng H, Wang Y, Jing Y, et al. PDK4 protein promotes tumorigenesis through activation of cAMP-response element-binding protein (CREB)-Ras homolog enriched in brain (RHEB)-mTORC1 signaling cascade. J Biol Chem 2014;289:29739-49.ArticlePubMedPMC
  • 54. Wu J, Zhao Y, Park YK, Lee JY, Gao L, Zhao J, et al. Loss of PDK4 switches the hepatic NF-κB/TNF pathway from prosurvival to pro-apoptosis. Hepatology 2018;68:1111-24.ArticlePubMedPMCPDF
  • 55. Connaughton S, Chowdhury F, Attia RR, Song S, Zhang Y, Elam MB, et al. Regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) gene expression by glucocorticoids and insulin. Mol Cell Endocrinol 2010;315:159-67.ArticlePubMedPMC
  • 56. Crossland H, Constantin-Teodosiu D, Gardiner SM, Greenhaff PL. Peroxisome proliferator-activated receptor γ agonism attenuates endotoxaemia-induced muscle protein loss and lactate accumulation in rats. Clin Sci (Lond) 2017;131:1437-47.ArticlePubMedPDF
  • 57. Attaix D, Combaret L, Bechet D, Taillandier D. Role of the ubiquitin-proteasome pathway in muscle atrophy in cachexia. Curr Opin Support Palliat Care 2008;2:262-6.ArticlePubMed
  • 58. Hartmann-Petersen R, Gordon C. Proteins interacting with the 26S proteasome. Cell Mol Life Sci 2004;61:1589-95.PubMedPMC
  • 59. Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 2001;294:1704-8.ArticlePubMed
  • 60. Clavel S, Coldefy AS, Kurkdjian E, Salles J, Margaritis I, Derijard B. Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are up-regulated in aged rat tibialis anterior muscle. Mech Ageing Dev 2006;127:794-801.ArticlePubMed
  • 61. Eddins MJ, Marblestone JG, Suresh Kumar KG, Leach CA, Sterner DE, Mattern MR, et al. Targeting the ubiquitin E3 ligase MuRF1 to inhibit muscle atrophy. Cell Biochem Biophys 2011;60:113-8.ArticlePubMedPDF
  • 62. Sinam IS, Chanda D, Thoudam T, Kim MJ, Kim BG, Kang HJ, et al. Pyruvate dehydrogenase kinase 4 promotes ubiquitinproteasome system-dependent muscle atrophy. J Cachexia Sarcopenia Muscle 2022;13:3122-36.ArticlePubMedPMCPDF
  • 63. Kanda F, Okuda S, Matsushita T, Takatani K, Kimura KI, Chihara K. Steroid myopathy: pathogenesis and effects of growth hormone and insulin-like growth factor-I administration. Horm Res 2001;56 Suppl 1:24-8.ArticlePubMedPDF
  • 64. Reincke M. Cushing syndrome associated myopathy: it is time for a change. Endocrinol Metab (Seoul) 2021;36:564-71.ArticlePubMedPMC
  • 65. Shen S, Liao Q, Liu J, Pan R, Lee SM, Lin L. Myricanol rescues dexamethasone-induced muscle dysfunction via a sirtuin 1-dependent mechanism. J Cachexia Sarcopenia Muscle 2019;10:429-44.ArticlePubMedPMCPDF
  • 66. Chen HH, Tsai LK, Liao KY, Wu TC, Huang YH, Huang YC, et al. Muscle-restricted nuclear receptor interaction protein knockout causes motor neuron degeneration through downregulation of myogenin at the neuromuscular junction. J Cachexia Sarcopenia Muscle 2018;9:771-85.ArticlePubMedPMCPDF
  • 67. Shi H, Verma M, Zhang L, Dong C, Flavell RA, Bennett AM. Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5. J Clin Invest 2013;123:2064-77.ArticlePubMedPMC
  • 68. Sacco A, Doyonnas R, Kraft P, Vitorovic S, Blau HM. Self-renewal and expansion of single transplanted muscle stem cells. Nature 2008;456:502-6.ArticlePubMedPMCPDF
  • 69. Adhikari A, Kim W, Davie J. Myogenin is required for assembly of the transcription machinery on muscle genes during skeletal muscle differentiation. PLoS One 2021;16:e0245618.ArticlePubMedPMC

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      The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4
      Diabetes Metab J. 2023;47(2):153-163.   Published online January 12, 2023
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    Kim MJ, Sinam IS, Siddique Z, Jeon JH, Lee IK. The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4. Diabetes Metab J. 2023;47(2):153-163.
    Received: Aug 31, 2022; Accepted: Nov 13, 2022

    Diabetes Metab J : Diabetes & Metabolism Journal
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