bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒04‒19
eighteen papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Appl Physiol Nutr Metab. 2020 Apr 14.
    Velayoudom-Cephise FL, Cano Sanchez M, Bercion S, Tessier F, Yu Y, Boulanger E, Neviere R.
      Background Accumulation of advanced glycation end products (AGE) and activation of receptor to AGE (RAGE) is implicated in the progression of pathologies associated with aging, chronic inflammation, diabetes and cellular stress. RAGE activation is also implicated in cardiovascular complications of type 2 diabetes, such as nephropathy, retinopathy, accelerated vascular diseases and cardiomyopathy. Studies investigating effects of AGE/RAGE axis activation on skeletal muscle oxidative stress / metabolism are more limited. Methods and Results We tested whether high fat feeding (HFD) would alter circulating AGE concentration, skeletal muscle AGE accumulation, and oxidative stress in wild type and RAGE deficient mice. Physiological significance of AGE/RAGE axis activation in mice under HFD was evaluated in terms of exercise tolerance, and mitochondrial respiratory chain complex activity. HFD elicited adiposity, abnormal fat distribution as well as oral glucose intolerance. HFD induced soleus muscle accumulation of Nɛ-carboxymethyl-lysine, increased carbonyl protein levels and impaired respiratory chain complex activity. Ablation of RAGE had no effects on weight gain and oral glucose tolerance in HFD mice. Peak exercise aerobic capacity and mitochondrial cytochrome c oxidase activity were restored in HFD RAGE-/- mice. Conclusions We concluded that RAGE signaling plays an important role in skeletal muscle homeostasis of mice under metabolic stress. Novelty bullets • High fat diet (HFD) in mice induces accumulation of advanced glycation end products (AGE), oxidative stress and mitochondrial dysfunction in the soleus muscle. • RAGE, the multi-ligand receptor of AGE, modulates oxidative stress and mitochondrial electron transport chain function in the soleus of HFD mice.
  2. Aging Cell. 2020 Apr 15. e13140
    Goljanek-Whysall K, Soriano-Arroquia A, McCormick R, Chinda C, McDonagh B.
      One of the key mechanisms underlying skeletal muscle functional deterioration during aging is disrupted mitochondrial dynamics. Regulation of mitochondrial dynamics is essential to maintain a healthy mitochondrial population and prevent the accumulation of damaged mitochondria; however, the regulatory mechanisms are poorly understood. We demonstrated loss of mitochondrial content and disrupted mitochondrial dynamics in muscle during aging concomitant with dysregulation of miR-181a target interactions. Using functional approaches and mito-QC assay, we have established that miR-181a is an endogenous regulator of mitochondrial dynamics through concerted regulation of Park2, p62/SQSTM1, and DJ-1 in vitro. Downregulation of miR-181a with age was associated with an accumulation of autophagy-related proteins and abnormal mitochondria. Restoring miR-181a levels in old mice prevented accumulation of p62, DJ-1, and PARK2, and improved mitochondrial quality and muscle function. These results provide physiological evidence for the potential of microRNA-based interventions for age-related muscle atrophy and of wider significance for diseases with disrupted mitochondrial dynamics.
    Keywords:  aging; miR-181a; mitophagy; p62; parkin; protein DJ-1; skeletal muscle
  3. Geroscience. 2020 Apr 16.
    Yeo D, Kang C, Ji LL.
      During aging, organs such as skeletal muscle and heart require sufficient NAD+ both as a coenzyme for oxidative-reductive electron transfer and as a substrate for multiple signaling pathways. Sirtuins (SIRTs), a family of NAD+-dependent deacetylase, play an important role in regulating mitochondrial homeostasis and antioxidant defense by deacetylating transcription factors and enzymes such as PGC-1α, p65, GCN5, and SOD2. However, age-related DNA damage and increased SASP activate PARP-1 and CD38, the enzymes competing with SIRTs for NAD+. Thus, it is important to know how aging alters intracellular NAD+ status and NAD+-depending enzyme expression in muscles. In this study, we report that the acetylation level of muscle protein pool, as well as major SIRTs target proteins (PGC-1α, GCN5, p65, and SOD2), was significantly increased in hindlimb and cardiac muscles of 24-month old mice compared with their 6-month old counterparts, despite the fact that most members of the SIRT family were upregulated with aging. Aging increased the protein content of PARP-1 and CD38, whereas decreased NAD+ levels in both skeletal and heart muscles. Aged muscles demonstrated clear signs of mitochondrial dysfunction, oxidative stress, and inflammation. Taken together, our data suggest that despite the upregulation of SIRTs, aged muscles suffered from NAD+ deficit partly due to the competition of elevated CD38 and PARP-1. The enhanced acetylation of several key proteins involved in broad cellular functions may contribute to the age-related muscle deterioration.
    Keywords:  Aging; CD38; Deacetylation; NAD+; PARP; SIRT; Skeletal muscle
  4. Exp Physiol. 2020 Apr 13.
    Nay K, Martin D, Orfila L, Saligaut D, Martin B, Horeau M, Cavey T, Kenawi M, Island ML, Ropert M, Loréal O, Koechlin-Ramonatxo C, Derbré F.
      NEW FINDINGS: What is the central question of this study? Could skeletal muscle be involved in microgravity-induced iron misdistribution by modulating hepcidin expression, the master regulator of iron metabolism? What is the main finding and its importance? We demonstrate in rats that hepcidin upregulation is not a transient adaptation associated with early exposure to microgravity, and that intermittent reloading does not limit microgravity-induced iron misdistribution despite a beneficial effect on soleus muscle wasting.ABSTRACT: In humans, exposure to microgravity during spaceflights causes muscle atrophy, iron storage changes, and iron availability reduction. We previously observed in rats that during simulated microgravity for 7 days, hepcidin plays a key role in iron misdistribution, and suggested that a crosstalk between skeletal muscle and liver could regulate hepcidin synthesis in this context. In the present study, we investigated in rats the medium-term effects of simulated microgravity on iron metabolism. We also tested whether intermittent reloading (IR) to target skeletal muscle atrophy efficiently limits iron misdistribution. To this purpose, Wistar rats underwent 14 days of hindlimb unloading (HU) combined or not with daily IR. At the end of this period, serum iron concentration and transferrin saturation were significantly reduced, whereas hepatic hepcidin mRNA was upregulated. However, the main signaling pathways involved in hepcidin synthesis in liver (BMP/SMAD, IL6/STAT3, and ERK1/2) were unaffected. Differently from what observed after 7 days of HU, iron concentration in spleen, liver and skeletal muscle was comparable between control and animals that underwent HU or HU+IR for 14 days. Despite its beneficial effect on soleus muscle atrophy and slow-to-fast myosin heavy chain distribution, IR did not significantly prevent iron availability reduction and hepcidin upregulation. Altogether, these results highlight that iron availability is durably reduced during longer exposure to simulated microgravity, and that the related hepcidin upregulation is not a transient adaptation to this condition. They also suggest that skeletal muscle does not necessarily play a key role in iron misdistribution occurring during simulated microgravity. This article is protected by copyright. All rights reserved.
    Keywords:  crosstalk; disuse; iron overload; myosin heavy chain; physical inactivity
  5. FASEB J. 2020 Apr 15.
    Ahn J, Ha TY, Ahn J, Jung CH, Seo HD, Kim MJ, Kim YS, Jang YJ.
      Dietary habits can alter the skeletal muscle performance and mass, and Undaria pinnatifida extracts are considered a potent candidate for improving the muscle mass and function. Therefore, in this study, we aimed to assess the effect of U pinnatifida extracts on exercise endurance and skeletal muscle mass. C57BL/6 mice were fed a 0.25% U pinnatifida extract-containing diet for 8 weeks. U pinnatifida extract-fed mice showed increased running distance, total running time, and extensor digitorum longus and gastrocnemius muscle weights. U pinnatifida extract supplementation upregulated the expression of myocyte enhancer factor 2C, oxidative muscle fiber markers such as myosin heavy chain 1 (MHC1), and oxidative biomarkers in the gastrocnemius muscles. Compared to the controls, U pinnatifida extract-fed mice showed larger mitochondria and increased gene and protein expression of molecules involved in mitochondrial biogenesis and oxidative phosphorylation, including nuclear respiratory factor 2 and mitochondrial transcription factor A. U pinnatifida extract supplementation also increased the mRNA expression of angiogenesis markers, including VEGFa, VEGFb, FGF1, angiopoietin 1, and angiopoietin 2, in the gastrocnemius muscles. Importantly, U pinnatifida extracts upregulated the estrogen-related receptor γ and peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α)/AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) networks, which are partially increased by fucoxanthin, hesperetin, and caffeic acid treatments. Collectively, U pinnatifida extracts enhance mitochondrial biogenesis, increase oxidative muscle fiber, and promote angiogenesis in skeletal muscles, resulting in improved exercise capacity and skeletal muscle mass. These effects are attributable to fucoxanthin, hesperetin, and caffeic acid, bioactive components of U pinnatifida extracts.
    Keywords:   Undaria pinnatifida ; fucoxanthin; mitochondria biogenesis; oxidative muscle remodeling; running endurance
  6. Br J Pharmacol. 2020 Apr 15.
    Forte M, Schirone L, Ameri P, Basso C, Catalucci D, Modica J, Chimenti C, Crotti L, Frati G, Rubattu S, Schiattarella GG, Torella D, Perrino C, Indolfi C, Sciarretta S, .
      The process of mitochondrial dynamics is emerging as a core player in cardiovascular homeostasis. This process refers to the coordinated cycles of biogenesis, fusion, fission and degradation to which mitochondria constantly undergo to maintain their integrity, distribution and size. These mechanisms represent an early response to mitochondrial stress, confining organelle portions that are irreversibly damaged and preserving mitochondrial function. Accumulating evidence demonstrates that impairment in mitochondrial dynamics leads to myocardial damage and cardiac disease progression in a variety of disease models, including pressure overload, ischemia/reperfusion and metabolic disturbance. These findings suggest that modulation of mitochondrial dynamics may be considered as a valid therapeutic strategy in cardiovascular diseases. In this review, we discuss the current evidence about the role of mitochondrial dynamics in cardiac pathophysiology, with a particular focus on the mechanisms underlying the development of cardiac hypertrophy and heart failure, metabolic and genetic cardiomyopathies, ischemia/reperfusion injury, atherosclerosis and ischemic stroke.
    Keywords:  fission; fusion; mitochondrial dynamics; cardiovascular diseases; mitophagy
  7. Front Physiol. 2020 ;11 259
    Vann CG, Osburn SC, Mumford PW, Roberson PA, Fox CD, Sexton CL, Johnson MR, Johnson JS, Shake J, Moore JH, Millevoi K, Beck DT, Badisa VLD, Mwashote BM, Ibeanusi V, Singh RK, Roberts MD.
      While high-load resistance training increases muscle hypertrophy, the intramuscular protein responses to this form of training remains largely unknown. In the current study, recreationally resistance-trained college-aged males (N = 15; mean ± SD: 23 ± 3 years old, 6 ± 5 years training) performed full-body, low-volume, high-load [68-90% of one repetition maximum (1RM)] resistance training over 10 weeks. Back squat strength testing, body composition testing, and a vastus lateralis biopsy were performed before (PRE) and 72 h after the 10-week training program (POST). Fiber type-specific cross-sectional area (fCSA), myofibrillar protein concentrations, sarcoplasmic protein concentrations, myosin heavy chain and actin protein abundances, and muscle tissue percent fluid were analyzed. The abundances of individual sarcoplasmic proteins in 10 of the 15 participants were also assessed using proteomics. Significant increases (p < 0.05) in type II fCSA and back squat strength occurred with training, although whole-body fat-free mass paradoxically decreased (p = 0.026). No changes in sarcoplasmic protein concentrations or muscle tissue percent fluid were observed. Myosin heavy chain protein abundance trended downward (-2.9 ± 5.8%, p = 0.069) and actin protein abundance decreased (-3.2 ± 5.3%, p = 0.034) with training. Proteomics indicated only 13 sarcoplasmic proteins were altered with training (12 up-regulated, 1 down-regulated, p < 0.05). Bioinformatics indicated no signaling pathways were affected, and proteins involved with metabolism (e.g., ATP-PCr, glycolysis, TCA cycle, or beta-oxidation) were not affected. These data comprehensively describe intramuscular protein adaptations that occur following 10 weeks of high-load resistance training. Although previous data from our laboratory suggests high-volume resistance training enhances the ATP-PCr and glycolytic pathways, we observed different changes in metabolism-related proteins in the current study with high-load training.
    Keywords:  actin; high-load training; myosin; proteomics; skeletal muscle
  8. Life Sci. 2020 Apr 12. pii: S0024-3205(20)30378-7. [Epub ahead of print] 117630
    Thirupathi A, Pinho RA, Chang YZ.
      Oxidative stress is the core of most pathological situations, and its attribution toward disease conversion is not yet well established. The adaptive capacity of a cell can overcome ROS-induced pathology. However, when a cell fails to extend its maximum adaptive capacity against oxidative stress, it could lead a cell to misbehave or defunct from its normal functions. Any type of physical activity can increase the cells' maximum adaptive capacity, but aging can limit this. However, whether aging is the initiating point of reducing cells' adaptive capacity against oxidative stress or oxidative stress can induce the aging process is a mystery, and it could be the key to solving several uncured diseases. Paradoxically, minimum ROS is needed for cellular homeostasis. Nevertheless, finding factors that can limit or nullify the production of ROS for cellular homeostasis is a million-dollar question. Regular physical exercise is considered to be one of the factors that can limit the production of ROS and increase the ROS-induced benefits in the cells through inducing minimum oxidative stress and increasing maximum adapting capacity against oxidative stress-induced damages. The type and intensity of exercise that can produce such positive effects in the cells remain unclear. Therefore, this review discusses how physical exercise can help to produce minimal positive oxidative stress in preventing skeletal muscle aging.
    Keywords:  Antioxidants; Muscle aging; Oxidative stress; Physical exercise; ROS
  9. Adv Exp Med Biol. 2020 ;1260 123-158
    Marzuca-Nassr GN, SanMartín-Calísto Y, Guerra-Vega P, Artigas-Arias M, Alegría A, Curi R.
      In the ordinary course of aging, individuals change their body composition, mainly reducing their skeletal muscle mass and increasing their fat mass. In association, muscle strength and functionality also decrease. The geriatric assessment allows knowing the baseline situation of the patients, determines the impact of diseases, and defines specific treatments. There are various tools to evaluate the health condition of older people. These tools include the assessment scales of necessary Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL), physical and functional assessment scales, and instruments that assess the cognitive state of the person. There are several strategies that have been proposed to combat skeletal muscle atrophy due to aging, such as physical exercise, nutritional supplements, or drugs. Some researchers have highlighted the efficacy of the combination of the mentioned strategies. In this chapter, we will focus only on physical exercise as a strategy to reduce skeletal muscle loss during aging.
    Keywords:  Activities of daily living; Elderly; Exercise; Muscle mass; Resistance training; Sarcopenia
  10. Nutrients. 2020 Apr 13. pii: E1079. [Epub ahead of print]12(4):
    Kim C, Hwang JK.
      Sarcopenia is a muscle disease featured by the loss of muscle mass and dysfunction with advancing age. The 5,7-dimethoxyflavone (DMF), a major flavone found in Kaempferia parviflora, has biological activities, including anti-diabetes, anti-obesity, and anti-inflammation. However, its anti-sarcopenic effect remains to be elucidated. This current study investigated the inhibitory activity of DMF on sarcopenia. Eighteen-month-old mice were orally administered DMF at the dose of 25 mg·kg-1·day-1 or 50 mg·kg-1·day-1 for 8 weeks. DMF not only stimulated grip strength and exercise endurance but also increased muscle mass and volume. Besides, DMF stimulated the phosphatidylinositol 3-kinase-Akt pathway, consequently activating the mammalian target of rapamycin-eukaryotic initiation factor 4E-binding protein 1-70-kDa ribosomal protein S6 kinase pathway for protein synthesis. DMF reduced the mRNA expression of E3 ubiquitin ligase- and autophagy-lysosomal-related genes involved in proteolysis via the phosphorylation of Forkhead box O3. DMF upregulated peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, nuclear respiratory factor 1, and mitochondrial transcription factor A along with the increase of relative mitochondrial DNA content. DMF alleviated inflammatory responses by reducing the tumor necrosis factor-alpha and interleukin-6 serum and mRNA levels. Collectively, DMF can be used as a natural agent to inhibit sarcopenia via improving protein turnover and mitochondria function.
    Keywords:  5,7-dimethoxyflavone; aging; sarcopenia; skeletal muscle
  11. Scand J Med Sci Sports. 2020 Apr 13.
    Vikne H, Strøm V, Hugo Pripp A, Gjøvaag T.
      The main objective of this systematic review was to examine the effect of reduced muscle activity on the relative number of type 1 muscle fibers (%) in the human vastus lateralis muscle. Other objectives were changes in type 2A and 2X percentages and muscle fiber cross-sectional area. We conducted systematic literature searches in eight databases and included studies assessing type 1 fiber percentage visualized by ATPase- or immunohistochemical staining before- and after a period (≥ 14 days) of reduced muscle activity. The reduced muscle activity models were detraining, leg unloading and bed rest. Forty-two studies comprising 451 participants were included. Effect sizes were calculated as the mean difference between baseline and follow-up and Generic Inverse Variance tests with random effects models was used for the weighted summary effect size. Overall, the mean type 1 muscle fiber percentage was significantly reduced after interventions (-1.94 %-points, 95 % CI [-3.37, -0.51], p = 0.008), with no significant differences between intervention models (p = 0.86). Meta-regression showed no effect of study duration on type 1 fiber percentage (p = 0.98). Conversely, the overall type 2X fiber percentage increased after reduced muscle activity (p < 0.001). The CSA of the muscle fiber types decreased after the study period (all p-values < 0.001) with greater reductions in type 2 than type 1 fibers (p < 0.001). The result of this meta-analysis display that the type 1 muscle fiber percentage decrease as a result of reduced muscle activity, although the effect size is relatively small.
    Keywords:  Type 1 muscle fibers; bed rest; cross-sectional area; detraining; histochemistry; immobilization; leg unloading; transformation
  12. FASEB J. 2020 Apr 11.
    Przanowska RK, Sobierajska E, Su Z, Jensen K, Przanowski P, Nagdas S, Kashatus JA, Kashatus DF, Bhatnagar S, Lukens JR, Dutta A.
      miR-206, miR-1a-1, and miR-1a-2 are induced during differentiation of skeletal myoblasts and promote myogenesis in vitro. miR-206 is required for skeletal muscle regeneration in vivo. Although this miRNA family is hypothesized to play an essential role in differentiation, a triple knock-out (tKO) of the three genes has not been done to test this hypothesis. We report that tKO C2C12 myoblasts generated using CRISPR/Cas9 method differentiate despite the expected derepression of the miRNA targets. Surprisingly, their mitochondrial function is diminished. tKO mice demonstrate partial embryonic lethality, most likely due to the role of miR-1a in cardiac muscle differentiation. Two tKO mice survive and grow normally to adulthood with smaller myofiber diameter, diminished physical performance, and an increase in PAX7 positive satellite cells. Thus, unlike other miRNAs important in other differentiation pathways, the miR-206 family is not absolutely essential for myogenesis and is instead a modulator of optimal differentiation of skeletal myoblasts.
    Keywords:  miR-1a-1; miR-1a-2; myogenesis; myomiRs; skeletal muscle differentiation
  13. Adv Exp Med Biol. 2020 ;1260 297-318
    Abiri B, Vafa M.
      The elderly population is increasing rapidly worldwide, and we are faced with the significant challenge for maintaining or improving physical activity, independence, and quality of life. Sarcopenia, the age-related decline of skeletal muscle mass, is characterized by loss of muscle quantity and quality resulting to a gradual slowing of movement, a decrease in strength and power, elevated risk of fall-related injury, and often frailty. Supplemental, hormonal, and pharmacological approaches have been attempted to attenuate sarcopenia but these have not achieved outstanding results. In this review, we summarize the current knowledge of nutrition-based therapies for counteracting sarcopenia.
    Keywords:  Aging; Diet; Exercise; Muscle atrophy; Nutrition; Sarcopenia
  14. Med Sci Sports Exerc. 2020 Apr 07.
    Adami A, Corvino RB, Calmelat RA, Porszasz J, Casaburi R, Rossiter HB.
      INTRODUCTION: Skeletal muscle atrophy, weakness, mitochondrial loss and dysfunction are characteristics of chronic obstructive pulmonary disease (COPD). It remains unclear whether muscle dysfunction is localized to the lower limbs, because findings are inconsistent in the few studies where upper and lower limb muscle performance properties were compared within an individual. This study determined whether muscle oxidative capacity is low in both upper and lower limbs of COPD patients compared with controls.METHODS: Oxidative capacity of the forearm and medial gastrocnemius were measured using near-infrared spectroscopy to determine the muscle O2 consumption recovery rate constant (k, min) in 20 COPD (GOLD 2/3/4, n=7/7/6) and 20 smokers with normal spirometry (CON). Muscle k is linearly proportional to oxidative capacity. Steps/day and vector magnitude units (VMU)/min were assessed using triaxial accelerometry. Differences between group and limb were assessed by 2-way ANOVA.
    RESULTS: There was a significant main effect of group (F=11.2, ηp=0.13, P=0.001): k was lower in both upper and lower limb muscles in COPD (1.01±0.17, 1.05±0.24 min) compared with CON (1.29±0.49, 1.54±0.60 min). There was no effect on k of limb (F=1.8, ηp=0.02, P=0.18) or group x limb interaction (P=0.35). VMU/min was significantly lower in COPD (-38%; P=0.042). Steps/day did not differ between COPD (4738±3194) and CON (6372±2107; P=0.286), although the difference exceeded a clinically important threshold (>600-1100 steps/day).
    CONCLUSION: Compared with CON, muscle oxidative capacity was lower in COPD in both upper (-20%) and lower (-30%) limbs. These data suggest that mitochondrial loss in COPD is not isolated to locomotor muscles.
  15. FASEB J. 2020 Apr 15.
    Li X, Yang L, Mao Z, Pan X, Zhao Y, Gu X, Eckel-Mahan K, Zuo Z, Tong Q, Hartig SM, Cheng X, Du G, Moore DD, Bellen HJ, Sesaki H, Sun K.
      Dynamin-Related-Protein 1 (DRP1) critically regulates mitochondrial and peroxisomal fission in multicellular organisms. However, the impact of DRP1 on other organelles, especially its direct influence on ER functions remains largely unclear. Here, we report that DRP1 translocates to endoplasmic reticulum (ER) in response to β-adrenergic stimulation. To further investigate the function of DRP1 on ER-lipid droplet (LD) dynamics and the metabolic subsequences, we generated an adipose tissue-specific DRP1 knockout model (Adipo-Drp1flx/flx ). We found that the LDs in adipose tissues of Adipo-Drp1flx/flx mice exhibited more unilocular morphology with larger sizes, and formed less multilocular structures upon cold exposure. Mechanistically, we discovered that abnormal LD morphology occurs because newly generated micro-LDs fail to dissociate from the ER due to DRP1 ablation. Conversely, the ER retention of LDs can be rescued by the overexpressed DRP1 in the adipocytes. The alteration of LD dynamics, combined with abnormal mitochondrial and autophagy functions in adipose tissue, ultimately lead to abnormalities in lipid metabolism in Adipo-Drp1flx/flx mice.
    Keywords:  ER retention; LD budding; LD morphology; energy expenditure; lipolysis
  16. Physiol Rep. 2020 Apr;8(7): e14411
    Shirai T, Aoki Y, Takeda K, Takemasa T.
      Concurrent training involves a combination of two different modes of training. In this study, we conducted an experiment by combining resistance and endurance training. The purpose of this study was to investigate the influence of the order of concurrent training on signal molecules in skeletal muscle. The phosphorylation levels of p70 S6 kinase, S6 ribosomal protein, and 4E-binding protein 1, which are related to hypertrophy signaling, increased significantly in the resistance-endurance order group as compared with in control group not the endurance-resistance order group. The gene expressions related to metabolism were not changed by the order of concurrent training. The mitochondrial respiratory chain complex was evaluated by western blot. Although both groups of concurrent training showed a significant increase in MTCO1, UQCRC2, and ATP5A protein levels, we could not detect a difference based on the order of concurrent training. In conclusion, a concurrent training approach involving resistance training before endurance training on the same day is an effective way to activate both mTOR signaling and mitochondria biogenesis.
    Keywords:  concurrent training; mTOR signaling; mitochondrial biogenesis; skeletal muscle
  17. FEBS Open Bio. 2020 Apr 17.
    Katiyar A, Fujimoto M, Tan K, Kurashima A, Srivastava P, Okada M, Takii R, Nakai A.
      The mitochondrial unfolded protein response (UPRmt ) is characterized by the transcriptional induction of mitochondrial chaperone and protease genes in response to impaired mitochondrial proteostasis, and is regulated by ATF5 and CHOP in mammalian cells. However, the detailed mechanisms underlying the UPRmt are currently unclear. Here, we show that HSF1 is required for activation of mitochondrial chaperone genes, including HSP60, HSP10, and mtHSP70, in mouse embryonic fibroblasts during inhibition of matrix chaperone TRAP1, protease Lon, or electron transfer complex 1 activity. HSF1 bound constitutively to mitochondrial chaperone gene promoters, and we observed that its occupancy was remarkably enhanced at different levels during the UPRmt . Furthermore, HSF1 supported maintenance of mitochondrial function under the same conditions. These results demonstrate that HSF1 is required for induction of mitochondrial chaperones during the UPRmt , and thus it may be one of the guardians of mitochondrial function under conditions of impaired mitochondrial proteostasis.
    Keywords:  HSF1; SSBP1; heat shock protein; mitochondria; proteostasis; proteotoxic stress
  18. Proc Natl Acad Sci U S A. 2020 Apr 17. pii: 201917948. [Epub ahead of print]
    Tavallaie M, Voshtani R, Deng X, Qiao Y, Jiang F, Collman JP, Fu L.
      Deregulation of mitochondrial dynamics leads to the accumulation of oxidative stress and unhealthy mitochondria; consequently, this accumulation contributes to premature aging and alterations in mitochondria linked to metabolic complications. We postulate that restrained mitochondrial ATP synthesis might alleviate age-associated disorders and extend healthspan in mammals. Herein, we prepared a previously discovered mitochondrial complex IV moderate inhibitor in drinking water and orally administered to standard-diet-fed, wild-type C57BL/6J mice every day for up to 16 mo. No manifestation of any apparent toxicity or deleterious effect on studied mouse models was observed. The impacts of an added inhibitor on a variety of mitochondrial functions were analyzed, such as respiratory activity, mitochondrial bioenergetics, and biogenesis, and a few age-associated comorbidities, including reactive oxygen species (ROS) production, glucose abnormalities, and obesity in mice. It was found that mitochondrial quality, dynamics, and oxidative metabolism were greatly improved, resulting in lean mice with a specific reduction in visceral fat plus superb energy and glucose homeostasis during their aging period compared to the control group. These results strongly suggest that a mild interference in ATP synthesis through moderation of mitochondrial activity could effectively up-regulate mitogenesis, reduce ROS production, and preserve mitochondrial integrity, thereby impeding the onset of metabolic syndrome. We conclude that this inhibitory intervention in mitochondrial respiration rectified the age-related physiological breakdown in mice by protecting mitochondrial function and markedly mitigated certain undesired primary outcomes of metabolic syndrome, such as obesity and type 2 diabetes. This intervention warrants further research on the treatment of metabolic syndrome of aging in humans.
    Keywords:  aging; cytochrome c oxidase; metabolic syndrome; mitochondria; mitogenesis