bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒05‒24
ten papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Diabetes Metab Syndr Obes. 2020 ;13 1417-1428
    Zhang Z, Cui D, Zhang T, Sun Y, Ding S.
      Purpose: Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are associated with metabolic diseases such as obesity and Type 2 diabetes mellitus (T2DM). Mitochondria and ER are connected via mitochondria-associated membranes (MAM) that are involved in glucose homeostasis and insulin resistance. We postulated that exercise might positively benefit T2DM-induced ER and mitochondrial dysfunction that might be associated with MAM.Materials and Methods: Mice were fed a high-fat diet and injected with streptozotocin (STZ) to create T2DM models. Glucose tolerance, mitochondrial quality, MAM quality, and ERS were investigated in diabetic mice after six weeks of swimming.
    Results: Type 2 DM induced decreased MAM quantity, impaired mitochondrial quality, and deteriorated ERS in skeletal muscle that led to endoplasmic reticulum-associated degradation (ERAD). Swimming alleviated strong ERS caused by T2DM. Importantly, MAM quantity was positively associated with mitochondrial function and tended to negatively correlate with the ERS branch, ATF6. Moreover, both ATF6 branches of ERS and ERAD were positively associated with the pIRE1α branch of ERS.
    Conclusion: Type 2 DM induced glucose intolerance, powerful ERS, and mitochondrial dysfunction associated with decreased amounts of MAM. Swimming improved glucose intolerance and selectively mitigated the ERS in skeletal muscle. Therefore, MAM quality and ATF6 might be novel and important targets for T2DM treatment. Endoplasmic reticulum stress might be an effective target of swimming to improve diabetes.
    Keywords:  ERS; MAM; T2DM; mitochondrial quality; skeletal muscle
  2. Genes (Basel). 2020 May 18. pii: E563. [Epub ahead of print]11(5):
    Jadiya P, Tomar D.
      Mitochondria serve as a hub for many cellular processes, including bioenergetics, metabolism, cellular signaling, redox balance, calcium homeostasis, and cell death. The mitochondrial proteome includes over a thousand proteins, encoded by both the mitochondrial and nuclear genomes. The majority (~99%) of proteins are nuclear encoded that are synthesized in the cytosol and subsequently imported into the mitochondria. Within the mitochondria, polypeptides fold and assemble into their native functional form. Mitochondria health and integrity depend on correct protein import, folding, and regulated turnover termed as mitochondrial protein quality control (MPQC). Failure to maintain these processes can cause mitochondrial dysfunction that leads to various pathophysiological outcomes and the commencement of diseases. Here, we summarize the current knowledge about the role of different MPQC regulatory systems such as mitochondrial chaperones, proteases, the ubiquitin-proteasome system, mitochondrial unfolded protein response, mitophagy, and mitochondria-derived vesicles in the maintenance of mitochondrial proteome and health. The proper understanding of mitochondrial protein quality control mechanisms will provide relevant insights to treat multiple human diseases.
    Keywords:  chaperones; mitochondria; mitochondria-associated degradation; mitochondrial protein quality control; mitochondrial unfolded protein response; mitophagy; protease; proteasome; proteome; ubiquitin
  3. J Muscle Res Cell Motil. 2020 May 21.
    Frankish BP, Najdovska P, Xu H, Wette SG, Murphy RM.
      This study reports that in rat skeletal muscle the proteins specifically responsible for mitochondrial dynamics, mitofusin-2 (MFN2) and mitochondrial dynamics protein 49 (MiD49), are higher (p < 0.05) in oxidative soleus (SOL) muscle compared with predominantly glycolytic extensor digitorum longus (EDL) muscle, but not seen for optic atrophy 1 (OPA1; p = 0.06). Markers of mitochondrial content, complex I component, NADH:Ubiquinone oxidoreductase subunit A9 (NDUFA9) and complex IV protein, cytochrome C oxidase subunit IV (COXIV; p < 0.05) were also higher in SOL compared with EDL muscle; however, there was no difference in mitochondrial content between muscles, as measured using a citrate synthase assay (p > 0.05). SOL and EDL muscles were compared between age-matched sedentary rats that were housed individually with (RUN) or without (SED) free-access to a running wheel for 12 weeks and showed no change in mitochondrial content, as examined by the abundances of NDUFA9 and COXIV proteins, as well as citrate synthase activity, in either muscle (p > 0.05). Compared to SED animals, MiD49 and OPA1 were not different in either EDL or SOL muscles, and MFN2 was higher in SOL muscles from RUN rats (p < 0.05). Overall, these findings reveal that voluntary wheel running is an insufficient stimulus to result in a significantly higher abundance of most markers of mitochondrial content or dynamics, and it is likely that a greater stimulus, such as either adding resistance to the wheel or an increase in running volume by using a treadmill, is required for mitochondrial adaptation in rat skeletal muscle.
    Keywords:  Chronic inactivity; Mitochondria; Mitochondrial dynamics; Voluntary wheel running
  4. Mech Ageing Dev. 2020 May 15. pii: S0047-6374(20)30058-0. [Epub ahead of print] 111262
    Gao HE, Wu DS, Sun L, Yang LD, Qiao YB, Ma S, Wu ZJ, Ruan L, Li FH.
      PURPOSE: This study aims to evaluate whether regular lifelong exercise has effects on age-related inflammatory cytokines, oxidative stress, and the skeletal muscle proteome.METHODS: Four groups of adult-aged (8-month-old) female Sprague Dawley rats were used: rats for which training was initiated at either 8 (8 M-MICT, moderate-intensity continuous training) or 18 months (18 M-MICT) and sedentary rats aged either 26 (26 M-SED) or 8 months (8M-SED), who served as aging and adult sedentary controls, respectively. Aged skeletal muscles were subjected to proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) and immunoblotting analyses.
    RESULTS: Age-related loss of physical performance and anti-inflammatory steroid levels were lowest in the 8 M-MICT group, while the anti-oxidative activities remained unchanged compared to 18 M-MICT rats. The proteomic analysis demonstrated an amelioration of age-related changes to muscle contraction, focal adhesion signaling, mitochondrial function, apoptosis and regeneration, anti-oxidation, and protein processing in the endoplasmic reticulum in the 8 M-MICT. Additionally, neurotrophin (BDNF) and AKT/FOXO signaling pathways were upregulated in 8 M-MICT rats compared to 26 M-SED.
    CONCLUSION: 8 M-MICT exhibited greater beneficial effects in ameliorating age-related inflammation and physical performance loss, compared to 18 M-MICT. The amelioration is potentially related to the upregulation of autophagy activities via BDNF/AKT signaling.
    Keywords:  aging; lifelong exercise; proteome; skeletal muscle
  5. Biochim Biophys Acta Mol Basis Dis. 2020 May 10. pii: S0925-4439(20)30179-4. [Epub ahead of print] 165834
    Simoes ICM, Morciano G, Lebiedzinska-Arciszewska M, Aguiari G, Pinton P, Potes Y, Wieckowski MR.
      Mitochondria-associated membranes (MAM), physical platforms that enable communication between mitochondria and the endoplasmic reticulum (ER), are enriched with many proteins and enzymes involved in several crucial cellular processes, such as calcium (Ca2+) homeostasis, lipid synthesis and trafficking, autophagy and reactive oxygen species (ROS) production. Accumulating studies indicate that tumor suppressors and oncogenes are present at these intimate contacts between mitochondria and the ER, where they influence Ca2+ flux between mitochondria and the ER or affect lipid homeostasis at MAM, consequently impacting cell metabolism and cell fate. Understanding these fundamental roles of mitochondria-ER contact sites as important domains for tumor suppressors and oncogenes can support the search for new and more precise anticancer therapies. In the present review, we summarize the current understanding of basic MAM biology, composition and function and discuss the possible role of MAM-resident oncogenes and tumor suppressors.
    Keywords:  Cancer; Endoplasmic reticulum; Mitochondria; Mitochondria-associated membranes (MAM); Oncogenes; Oncosuppressors
  6. iScience. 2020 Apr 29. pii: S2589-0042(20)30301-1. [Epub ahead of print]23(5): 101116
    Gansemer ER, McCommis KS, Martino M, King-McAlpin AQ, Potthoff MJ, Finck BN, Taylor EB, Rutkowski DT.
      Many metabolic diseases disrupt endoplasmic reticulum (ER) homeostasis, but little is known about how metabolic activity is communicated to the ER. Here, we show in hepatocytes and other metabolically active cells that decreasing the availability of substrate for the tricarboxylic acid (TCA) cycle diminished NADPH production, elevated glutathione oxidation, led to altered oxidative maturation of ER client proteins, and attenuated ER stress. This attenuation was prevented when glutathione oxidation was disfavored. ER stress was also alleviated by inhibiting either TCA-dependent NADPH production or Glutathione Reductase. Conversely, stimulating TCA activity increased NADPH production, glutathione reduction, and ER stress. Validating these findings, deletion of the Mitochondrial Pyruvate Carrier-which is known to decrease TCA cycle activity and protect the liver from steatohepatitis-also diminished NADPH, elevated glutathione oxidation, and alleviated ER stress. Together, our results demonstrate a novel pathway by which mitochondrial metabolic activity is communicated to the ER through the relay of redox metabolites.
    Keywords:  biological sciences; cell biology; functional aspects of cell biology
  7. J Cell Biol. 2020 Jun 01. pii: e202005084. [Epub ahead of print]219(6):
    Ali L, Haynes CM.
      In this issue, Liu et al. (2019. J. Cell. Biol. find that the inhibition of mitochondrial ribosomes in combination with impaired mitochondrial fission or fusion increases C. elegans lifespan by activating the transcription factor HLH-30, which promotes lysosomal biogenesis.
  8. Am J Physiol Regul Integr Comp Physiol. 2020 May 20.
    Lundberg TR, Martínez-Aranda LM, Sanz G, Hansson B, von Walden F, Tesch PA, Fernandez-Gonzalo R.
      The current study explored whether the marked hypertrophic response noted with a short-term unilateral concurrent exercise paradigm was associated with more prominent changes in myonuclei accretion, ribosome biogenesis and capillarization compared to resistance exercise alone (RE). Ten men (age 25±4yr) performed aerobic and resistance exercise (AE+RE) for one leg, while the other leg did RE. Muscle biopsies were obtained before and after 5 weeks of training and subjected to fiber-type specific immunohistochemical analysis, and quantification of total RNA content and mRNA/rRNA transcript abundance. Type-II fiber cross-sectional area (CSA) increased with both AE+RE (22%) and RE (16%), while type-I fiber CSA increased mainly with AE+RE (16%). The change-score tended to differ between legs for type-I CSA (P=0.099), and the increase in smallest fiber diameter was greater in AE+RE than RE (P=0.029). The number of nuclei per fiber increased after AE+RE in both fiber types, and this increase was greater (P=0.027) than after RE. A strong correlation was observed between changes in number of nuclei per fiber and fiber CSA in both fiber types, for both AE+RE and RE (r>0.8;P<0.004). RNA content increased after AE+RE (24%;P=0.019), but the change-scores did not differ across legs. The capillary variables generally increased in both fiber types, with no difference across legs. In conclusion, the accentuated hypertrophic response to AE+RE was associated with more pronounced myonuclear accretion, which was strongly correlated with the degree of fiber hypertrophy. This suggests that myonuclear accretion could play a role in facilitating muscle hypertrophy also during very short training periods.
    Keywords:  Angiogenesis; Endurance exercise; Human muscle; Resistance exercise; Ribosome biogenesis
  9. Diabetes. 2020 May 21. pii: db191074. [Epub ahead of print]
    Lantier L, Williams AS, Williams IM, Guerin A, Bracy DP, Goelzer M, Foretz M, Viollet B, Hughey CC, Wasserman DH.
      Insulin resistance due to overnutrition places a burden on energy-producing pathways in skeletal muscle (SkM). Nevertheless, energy state is not compromised. The hypothesis that the energy sensor AMP-activated protein kinase (AMPK) is necessary to offset the metabolic burden of overnutrition was tested using chow-fed and high fat (HF)-fed SkM-specific AMPKα1α2 knockout (mdKO) mice and AMPKα1α2lox/lox littermates (WT). Lean mdKO and WT mice were phenotypically similar. HF-fed mice were equally obese and maintained lean mass regardless of genotype. Results did not support the hypothesis that AMPK is protective during overnutrition. Paradoxically, mdKO mice were more insulin sensitive. Insulin-stimulated SkM glucose uptake was ∼two-fold greater in mdKO mice in vivo. Furthermore, insulin signaling, SkM GLUT4 translocation, hexokinase activity, and glycolysis were increased. AMPK and insulin signaling intersect at mTOR, a critical node for cell proliferation and survival. Basal mTOR activation was reduced by 50% in HF-fed mdKO mice, but was normalized by insulin-stimulation. Mitochondrial function was impaired in mdKO mice, but energy charge was preserved by AMP deamination. Results show a surprising reciprocity between SkM AMPK signaling and insulin action that manifests with diet-induced obesity, as insulin action is preserved to protect fundamental energetic processes in the muscle.
  10. J Clin Invest. 2020 May 19. pii: 136167. [Epub ahead of print]
    Bengoechea R, Findlay AR, Bhadra AK, Shao H, Stein KC, Pittman SK, Daw J, Gestwicki JE, True HL, Weihl CC.
      Dominant mutations in the HSP70 co-chaperone DNAJB6 cause a late onset muscle disease termed limb girdle muscular dystrophy type D1 (LGMDD1), which is characterized by protein aggregation and vacuolar myopathology. Disease mutations reside within the G/F domain of DNAJB6, but the molecular mechanisms underlying dysfunction are not well understood. Using yeast, cell culture, and mouse models of LGMDD1, we found that the toxicity associated with disease-associated DNAJB6 required its interaction with HSP70, and that abrogating this interaction genetically or with small molecules was protective. In skeletal muscle, DNAJB6 localizes to the Z-disc with HSP70. Whereas HSP70 normally diffused rapidly between the Z-disc and sarcoplasm, the rate of HSP70's diffusion in LGMDD1 mouse muscle was diminished likely because it has an unusual affinity for the Z-disc and mutant DNAJB6. Treating LGMDD1 mice with a small molecule inhibitor of the DNAJ-HSP70 complex re-mobilized HSP70, improved strength and corrected myopathology. These data support a model in which LGMDD1 mutations in DNAJB6 are a gain-of-function disease that is, counter-intuitively, mediated via HSP70 binding. Thus, therapeutic approaches targeting HSP70:DNAJB6 may be effective in treating this inherited muscular dystrophy.
    Keywords:  Cell Biology; Chaperones; Muscle Biology; Protein misfolding; Skeletal muscle