bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒09‒20
seven papers selected by
Rafael Antonio Casuso Pérez
University of Granada


  1. FASEB Bioadv. 2020 Sep;2(9): 538-553
    Roy A, Sharma AK, Nellore K, Narkar VA, Kumar A.
      Skeletal muscle atrophy is debilitating consequence of a large number of chronic disease states, aging, and disuse conditions. Skeletal muscle mass is regulated through coordinated activation of a number of signaling cascades. Transforming growth factor-β activated kinase 1 (TAK1) is a central kinase that mediates the activation of multiple signaling pathways in response to various growth factors, cytokines, and microbial products. Accumulating evidence suggests that TAK1 promotes skeletal muscle growth and essential for the maintenance of muscle mass in adults. Targeted inactivation of TAK1 leads to severe muscle wasting and kyphosis in mice. However, the mechanisms by which TAK1 prevents loss of muscle mass remain poorly understood. Through generation of inducible skeletal muscle-specific Tak1-knockout mice, we demonstrate that targeted ablation of TAK1 disrupts redox signaling leading to the accumulation of reactive oxygen species and loss of skeletal muscle mass and contractile function. Suppression of oxidative stress using Trolox improves muscle contractile function and inhibits the activation of catabolic signaling pathways in Tak1-deficient muscle. Moreover, Trolox inhibits the activation of ubiquitin-proteasome system and autophagy markers in skeletal muscle of Tak1-deficient mice. Furthermore, inhibition of oxidative stress using Trolox prevents the slow-to-fast type fiber transition and improves mitochondrial respiration in skeletal muscle of Tak1-deficient mice. Overall, our results demonstrate that TAK1 maintains skeletal muscle mass and health through redox homeostasis.
    Keywords:  TAK1; autophagy; cachexia; signaling; skeletal muscle wasting; ubiquitin‐proteasome system
    DOI:  https://doi.org/10.1096/fba.2020-00043
  2. Cell. 2020 Sep 15. pii: S0092-8674(20)31081-3. [Epub ahead of print]
    Reddy A, Bozi LHM, Yaghi OK, Mills EL, Xiao H, Nicholson HE, Paschini M, Paulo JA, Garrity R, Laznik-Bogoslavski D, Ferreira JCB, Carl CS, Sjøberg KA, Wojtaszewski JFP, Jeppesen JF, Kiens B, Gygi SP, Richter EA, Mathis D, Chouchani ET.
      In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release. Upon secretion, succinate signals via its cognate receptor SUCNR1 in non-myofibrillar cells in muscle tissue to control muscle-remodeling transcriptional programs. This succinate-SUCNR1 signaling is required for paracrine regulation of muscle innervation, muscle matrix remodeling, and muscle strength in response to exercise training. In sum, we define a bioenergetic sensor in muscle that utilizes intracellular pH and succinate to coordinate tissue adaptation to exercise.
    Keywords:  SUCNR1; exercise; innervation; muscle; succinate
    DOI:  https://doi.org/10.1016/j.cell.2020.08.039
  3. J Appl Physiol (1985). 2020 Sep 17.
    Rosa-Caldwell ME, Lim S, Haynie WS, Jansen LT, Westervelt LC, Amos MG, Washington TA, Greene NP.
      Muscle atrophy is a significant moderator for disease prognosis; as such, interventions to mitigate disuse-induced muscle loss are imperative to improve clinical interventions. Mitochondrial deteriorations may underlie disuse-induced myopathies; therefore, improving mitochondrial quality may be an enticing therapeutic intervention. However, different mitochondrial-based treatments may have divergent impacts on the prognosis of disuse atrophy. Therefore, the purpose of this study was to investigate different mitochondria-centered interventions during disuse atrophy in hindlimb unloaded male and female mice.METHODS: Male and female mice overexpressing PGC-1α (PGC-1α) or mitochondrially-targeted catalase (MCAT) and their respective wildtype (WT) littermate controls were hindlimb unloaded for 7 days to induce disuse atrophy or allowed normal ambulatory activity (cage control; CON). After designated interventions, animals were euthanized and tissues collected for measures of mitochondrial quality control and protein turnover.
    RESULTS: While PGC-1α overexpression mitigated ubiquitin-proteasome activation (MuRF1 and Atrogin mRNA content), this did not correspond to phenotypic protections from disuse-induced atrophy. Rather, PGC-1α mice appeared to have a greater reliance on autophagic protein breakdown compared to WT. In MCAT mice, females exhibited a mitigated response to disuse atrophy; however, this effect was not noted in males. Despite these phenotypic differences, there were no clear cellular signaling differences between MCAT hindlimb unloaded females and MCAT fully loaded females.
    CONCLUSION: PGC-1α overexpression does not protect against phenotypic alterations during disuse atrophy but appears to shift catabolic pathways moderating atrophy. However, increased mitochondrially-targeted catalase activity appears to blunt disuse atrophy within highly oxidative muscles specifically in female mice.
    Keywords:  PGC1α; catabolism; females; mitochondria; muscle atrophy
    DOI:  https://doi.org/10.1152/japplphysiol.00407.2020
  4. Biochim Biophys Acta Mol Cell Res. 2020 Sep 11. pii: S0167-4889(20)30212-3. [Epub ahead of print] 118854
    Patten DA, McGuirk S, Anilkumar U, Antoun G, Gandhi K, Parmar G, Iqbal MA, Wong J, Richardson RB, St-Pierre J, Slack RS, Harper ME.
      Mitochondria are highly dynamic organelles. Alterations in mitochondrial dynamics are causal or are linked to numerous neurodegenerative, neuromuscular, and metabolic diseases. It is generally thought that cells with altered mitochondrial structure are prone to mitochondrial dysfunction, increased reactive oxygen species generation and widespread oxidative damage. The objective of the current study was to investigate the relationship between mitochondrial dynamics and the master cellular antioxidant, glutathione (GSH). We reveal that mouse embryonic fibroblasts (MEFs) lacking the mitochondrial fusion machinery display elevated levels of GSH, which limits oxidative damage. Moreover, targeted metabolomics and 13C isotopic labeling experiments demonstrate that cells lacking the inner membrane fusion GTPase OPA1 undergo widespread metabolic remodeling altering the balance of citric acid cycle intermediates and ultimately favoring GSH synthesis. Interestingly, the GSH precursor and antioxidant n-acetylcysteine did not increase GSH levels in OPA1 KO cells, suggesting that cysteine is not limiting for GSH production in this context. Post-mitotic neurons were unable to increase GSH production in the absence of OPA1. Finally, the ability to use glycolysis for ATP production was a requirement for GSH accumulation following OPA1 deletion. Thus, our results demonstrate a novel role for mitochondrial fusion in the regulation of GSH synthesis, and suggest that cysteine availability is not limiting for GSH synthesis in conditions of mitochondrial fragmentation. These findings provide a possible explanation for the heightened sensitivity of certain cell types to alterations in mitochondrial dynamics.
    Keywords:  Mitofusin 1 & 2; Optic Atrophy 1; glutathione; metabolism; mitochondrial dynamics; mitochondrial fusion
    DOI:  https://doi.org/10.1016/j.bbamcr.2020.118854
  5. JCI Insight. 2020 Sep 17. pii: 141246. [Epub ahead of print]
    Lewsey SC, Weiss K, Schär M, Zhang Y, Bottomley PA, Samuel TJ, Xue QL, Steinberg A, Walston J, Gerstenblith G, Weiss RG.
      BACKGROUND: Physical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies, but their presence or link to EI in the frail older adult is unknown.METHODS: Three groups of ambulatory, community-dwelling adults with no history of significant coronary disease were studied: frail, older individuals (FO, 81±2.7 years, mean±SEM), non-frail, older individuals (NFO, 79±2.0 years), and healthy middle-aged controls (CONT, 51±2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31P magnetic resonance (MR) techniques during graded, multistage plantar flexion exercise (PFE). EI was quantified by six-minute walk and peak oxygen consumption during cardiopulmonary testing (peak-VO2).
    RESULTS: During graded exercise, frail older (FO), non-frail older (NFO), and healthy middle-aged individuals all fatigued at similar SM HEP levels measured by 31P MR. However, FO fatigued fastest with several-fold higher rates of PFE-induced HEP decline, which correlated closely with shorter exercise duration in the MR scanner and with six-minute walk distance and lower peak oxygen consumption on cardiopulmonary testing (p<0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI.
    CONCLUSIONS: Several-fold faster skeletal muscle energetic decline during exercise occurs in frail older individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations.
    Keywords:  Aging; Bioenergetics; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.141246
  6. Acta Physiol (Oxf). 2020 Sep 13. e13557
    Monti E, Toniolo L, Marcucci L, Bondì M, Martellato I, Šimunič B, Toninello P, Franchi MV, Narici MV, Reggiani C.
      AIM: Skeletal muscles of Body Builders (BB) represent an interesting model to study muscle mass gains in response to high volume resistance training. It is debated whether muscle contractile performance improves in proportion to mass. Here we aim to assess whether muscle hypertrophy does not occur at the expense of performance.METHODS: 6 BB and 6 untrained controls (CTRL) were recruited. Cross Sectional Area (CSA) and maximum voluntary contraction (MVC) of quadriceps femoris muscle (QF) and CSA and architecture of vastus lateralis (VL) were determined. Moreover, a biopsy was taken from VL mid-portion and single fibres were analysed.
    RESULTS: QF CSA and MVC were 32% (n.s., P=.052) and 58% (P=.009) higher in BB than in CTRL, respectively. VL CSA was 37% higher in BB (P=.030). Fast 2A fibres CSA was 24% (P=.048) greater in BB than in CTRL, when determined in immunostained sections of biopsy samples. Single permeabilized fast fibres CSA was 37% (n.s., P=.052) higher in BB than in CTRL, and their force was slightly higher in BB (n.s.), while specific tension (P0 ) was 19% (P=.024) lower. The lower P0 was not explained neither by lower myosin content nor by impaired calcium diffusion. Conversely, the swelling due to skinning-induced permeabilization was different and, when used to correct P0 , differences between populations disappeared.
    CONCLUSIONS: The results show that high degree of muscle hypertrophy is not detrimental for force generation capacity, as increases in fibre size and force are strictly proportional once the differential swelling response is accounted for.
    Keywords:  Skeletal muscles; fibre swelling; force and tension development; hypertrophy; isometric contraction; single muscle fibres
    DOI:  https://doi.org/10.1111/apha.13557
  7. J Cell Physiol. 2020 Sep 15.
    Gao M, Qin Y, Li A, Wei S, Liu B, Tian X, Gong G.
      The previous research has shown that mitochondrial flash (mitoflash) genesis are functionally and mechanistically integrated with mitochondrial electron transport chain (ETC) energy metabolism. However, the response of mitoflash to superoxide is not entirely consistent with the response of MitoSOX Red. The generation mechanism of mitoflash is still unclear. Here, we investigated mitoflash activities, using the different combinations of ETC substrates and inhibitors, in permeabilized cardiomyocytes or hearts. We found that blocking the complete electron flow, from Complex I to IV, with any one of ETC inhibitors including rotenone (Rot), antimycin A (AntA), myxothiazol (Myxo), stigmatellin, and sodium cyanide, will lead to the abolishment of mitoflashes triggered by substrates in adult permeabilized cardiomyocytes. However, Myxo boosted mitoflashes triggered by the reverse electron of N,N,N',N'-tetramethyl-p-phenylenediamine/ascorbate. Moreover, Rot and AntA furtherly enhanced mitoflash activity rather than depressed it, suggesting that mitoflashes generated at the Complex III Qo site. Meanwhile, the inhibition of Complex III protein expression resulted in the activity of Complex III decrease, which decreased mitoflash frequency. The function defect (no change of protein level) of the Qo site of Complex III in aging hearts augmented mitoflash generation confirmed the Qo site function was critical to mitoflash genesis. Thus, our results indicate that mitoflash detected by circularly permuted yellow fluorescent protein is generated at the Qo site of Complex III.
    Keywords:  Qo site; deficiency; mitochondrial function; mitoflash; oxidative stress
    DOI:  https://doi.org/10.1002/jcp.30059