bims-misrem 2020-12-06 papers

bims-misrem

Biomed News

on Mitochondria and sarcoplasmic reticulum in muscle mass

Issue of 2020–12–06
eight papers selected by
Rafael Antonio Casuso Pérez, University of Granada

Human skeletal muscle mitochondrial dynamics in relation to oxidative capacity and insulin sensitivity.
Maintenance of contractile force and increased fatigue resistance in slow-twitch skeletal muscle of mice fed a high-fat diet.
Cardiovascular health and mitochondrial function: testing an association.
Supercomplex formation boosts respiration.
The molecular complexity of the Mitochondrial Calcium Uniporter.
Cellular proteostasis decline in human senescence.
Reduced reticulum-mitochondria Ca2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy.
Type-2 muscle fiber atrophy is associated with sarcopenia in elderly men with hip fracture.

Diabetologia. 2020 Nov 30.

Human skeletal muscle mitochondrial dynamics in relation to oxidative capacity and insulin sensitivity.

Alexandre Houzelle, Johanna A Jörgensen, Gert Schaart, Sabine Daemen, Nynke van Polanen, Ciarán E Fealy, Matthijs K C Hesselink, Patrick Schrauwen, Joris Hoeks.

   AIMS/HYPOTHESIS: Mitochondria operate in networks, adapting to external stresses and changes in cellular metabolic demand and are subject to various quality control mechanisms. On the basis of these traits, we here hypothesise that the regulation of mitochondrial networks in skeletal muscle is hampered in humans with compromised oxidative capacity and insulin sensitivity.
METHODS: In a cross-sectional design, we compared four groups of participants (selected from previous studies) ranging in aerobic capacity and insulin sensitivity, i.e. participants with type 2 diabetes (n = 11), obese participants without diabetes (n = 12), lean individuals (n = 10) and endurance-trained athletes (n = 12); basal, overnight fasted muscle biopsies were newly analysed for the current study and we compared the levels of essential mitochondrial dynamics and quality control regulatory proteins in skeletal muscle tissue.
RESULTS: Type 2 diabetes patients and obese participants were older than lean participants and athletes (58.6 ± 4.0 and 56.7 ± 7.2 vs 21.8 ± 2.5 and 25.1 ± 4.3 years, p < 0.001, respectively) and displayed a higher BMI (32.4 ± 3.7 and 31.0 ± 3.7 vs 22.1 ± 1.8 and 21.0 ± 1.5 kg/m2, p < 0.001, respectively) than lean individuals and endurance-trained athletes. Fission protein 1 (FIS1) and optic atrophy protein 1 (OPA1) protein content was highest in muscle from athletes and lowest in participants with type 2 diabetes and obesity, respectively (FIS1: 1.86 ± 0.79 vs 0.79 ± 0.51 AU, p = 0.002; and OPA1: 1.55 ± 0.64 vs 0.76 ± 0.52 AU, p = 0.014), which coincided with mitochondrial network fragmentation in individuals with type 2 diabetes, as assessed by confocal microscopy in a subset of type 2 diabetes patients vs endurance-trained athletes (n = 6). Furthermore, lean individuals and athletes displayed a mitonuclear protein balance that was different from obese participants and those with type 2 diabetes. Mitonuclear protein balance also associated with heat shock protein 60 (HSP60) protein levels, which were higher in athletes when compared with participants with obesity (p = 0.048) and type 2 diabetes (p = 0.002), indicative for activation of the mitochondrial unfolded protein response. Finally, OPA1, FIS1 and HSP60 correlated positively with aerobic capacity (r = 0.48, p = 0.0001; r = 0.55, p < 0.001 and r = 0.61, p < 0.0001, respectively) and insulin sensitivity (r = 0.40, p = 0.008; r = 0.44, p = 0.003 and r = 0.48, p = 0.001, respectively).
CONCLUSIONS/INTERPRETATION: Collectively, our data suggest that mitochondrial dynamics and quality control in skeletal muscle are linked to oxidative capacity in humans, which may play a role in the maintenance of muscle insulin sensitivity. CLINICAL TRIAL REGISTRY: numbers NCT00943059, NCT01298375 and NL1888 Graphical abstract.

Keywords:  Fission, FIS1; Fusion; HSP60; Insulin sensitivity; Mitochondria; OPA1; Oxidative phosphorylation; Skeletal muscle

DOI:  https://doi.org/10.1007/s00125-020-05335-w
J Appl Physiol (1985). 2020 Dec 03.

Maintenance of contractile force and increased fatigue resistance in slow-twitch skeletal muscle of mice fed a high-fat diet.

Hiroaki Eshima, Yoshifumi Tamura, Saori Kakehi, Ryo Kakigi, Ryuzo Kawamori, Hirotaka Watada.

  Consumption of a high-fat diet (HFD) significantly increases exercise endurance performance during treadmill running. However, whether HFD consumption increases endurance capacity via enhanced muscle fatigue resistance has not been clarified. In this study, we investigated the effects of HFDs on contractile force and fatigue resistance of slow-twitch dominant muscles. The soleus (SOL) muscle of male C57BL/6J mice fed an HFD (60% kcal from fat) or a low-fat diet (LFD) for 12 weeks was analyzed. Muscle contractile force was measured under resting conditions and during fatigue induced by repeated tetanic contractions (100 Hz, 50 contractions, 2-second intervals). Differences in muscle twitch or tetanic force were not evident between HFD and LFD groups whereas fatigue resistance was higher for the entire end-stage period in the HFD groups. The SOL muscle of HFD-fed mice showed increased levels of markers related to oxidative capacity such as succinate dehydrogenase and citrate synthase activity. In addition, electron microscopy analyses indicated that the total number of mitochondria and mitochondrial volume density increased in the SOL muscle of the HFD groups. These findings suggest that HFD consumption induces increased muscle fatigue resistance in slow-twitch dominant muscle fibers. This effect of HFD may be related to elevated oxidative enzyme activity, high mitochondrial content, or both.

Keywords:  Contractile function; Fatigue resistance; Mitochondria; slow-twitch muscle

DOI:  https://doi.org/10.1152/japplphysiol.00218.2020
J Gerontol A Biol Sci Med Sci. 2020 Nov 29. pii: glaa297. [Epub ahead of print]

Cardiovascular health and mitochondrial function: testing an association.

Marta Zampino, Richard G Spencer, Kenneth W Fishbein, Eleanor M Simonsick, Luigi Ferrucci.

   BACKGROUND: Although mitochondrial dysfunction appears to be a contributing factor in the pathogenesis of cardiovascular and metabolic diseases, empirical data on this association are still lacking. This study evaluSated whether mitochondrial oxidative capacity, as assessed by phosphorus magnetic resonance spectroscopy, was associated with cardiovascular risk, as estimated by the Framingham Risk Score (FRS), and with a clinical history of cardiovascular disease (CVD), in community-dwelling adults.
METHODS: 616 subjects from the Baltimore Longitudinal Study on Aging (mean age 66 years) underwent a comprehensive clinical evaluation. Mitochondrial oxidative capacity in skeletal muscle was assessed as post-exercise phosphocreatine recovery time constant by phosphorus magnetic resonance spectroscopy. Multivariate regression models were employed to determine the cross-sectional association of mitochondrial oxidative capacity with FRS and history of CVD.
RESULTS: decreased mitochondrial oxidative capacity was strongly associated with higher FRS independent of age, body composition and physical activity. Lower oxidative capacity was also associated with a history of positive of CVD and higher number of CVD events.
CONCLUSIONS: we speculate that the observed association could reflect the effect of an excessive production of oxidative species by dysfunctional mitochondria. Furthermore, decreased energy production could hamper the functionality of heart and vessels. In turn, a malfunctioning cardiovascular apparatus could fail to deliver the oxygen necessary for optimal mitochondrial energy production, therefore creating a vicious cycle. Longitudinal studies are necessary to ascertain the directionality of the association and the eventual presence of common pathogenetic roots. In conclusion, mitochondria could represent an important target for intervention in cardiovascular health.

Keywords:  Cardiovascular; metabolism; oxidative stress; phosphorus magnetic resonance spectroscopy

DOI:  https://doi.org/10.1093/gerona/glaa297
EMBO Rep. 2020 Dec 03. e51830

Supercomplex formation boosts respiration.

Fabian den Brave, Thomas Becker.

Mitochondrial respiratory chain complexes associate in supercomplexes, but the physiological role of these assemblies remains controversial. Recent studies in EMBO Reports reveal that supercomplexes promote metabolic fitness. Berndtsson et al (2020) demonstrate that supercomplex formation enhances electron transport by reducing the distance for diffusion of cytochrome c between cytochrome bc1 complex and cytochrome c oxidase and thereby increases competitive fitness in yeast. Similarly, Garcia-Poyatos et al (2020) report that zebrafish lacking the supercomplex assembly factor SCAF1 display a reduced growth and decreased female fertility.

DOI: https://doi.org/10.15252/embr.202051830
Cell Calcium. 2020 Nov 22. pii: S0143-4160(20)30164-0. [Epub ahead of print]93 102322

The molecular complexity of the Mitochondrial Calcium Uniporter.

Simona Feno, Rosario Rizzuto, Anna Raffaello, Denis Vecellio Reane.

  The role of mitochondria in regulating cellular Ca2+ homeostasis is crucial for the understanding of different cellular functions in physiological and pathological conditions. Nevertheless, the study of this aspect was severely limited by the lack of the molecular identity of the proteins responsible for mitochondrial Ca2+ uptake. In 2011, the discovery of the gene encoding for the Mitochondrial Calcium Uniporter (MCU), the selective channel responsible for mitochondrial Ca2+ uptake, gave rise to an explosion of studies aimed to characterize the composition, the regulation of the channel and its pathophysiological roles. Here, we summarize the recent discoveries on the molecular structure and composition of the MCU complex by providing new insights into the mechanisms that regulate MCU channel activity.

Keywords:  Calcium homeostasis; Mitochondria; Mitochondrial Calcium Uniporter

DOI:  https://doi.org/10.1016/j.ceca.2020.102322
Proc Natl Acad Sci U S A. 2020 Nov 30. pii: 202018138. [Epub ahead of print]

Cellular proteostasis decline in human senescence.

Niv Sabath, Flonia Levy-Adam, Amal Younis, Kinneret Rozales, Anatoly Meller, Shani Hadar, Sharon Soueid-Baumgarten, Reut Shalgi.

  Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.

Keywords:  UPR; chaperones; heat shock response; protein homeostasis; senescence

DOI:  https://doi.org/10.1073/pnas.2018138117
Basic Res Cardiol. 2020 Nov 30. 115(6): 74

Reduced reticulum-mitochondria Ca2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy.

Maya Dia, Ludovic Gomez, Helene Thibault, Nolwenn Tessier, Christelle Leon, Christophe Chouabe, Sylvie Ducreux, Noelle Gallo-Bona, Emily Tubbs, Nadia Bendridi, Stephanie Chanon, Aymeric Leray, Lucid Belmudes, Yohann Couté, Mazen Kurdi, Michel Ovize, Jennifer Rieusset, Melanie Paillard.

  Type 2 diabetic cardiomyopathy features Ca2+ signaling abnormalities, notably an altered mitochondrial Ca2+ handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca2+ homeostasis, the reticulum-mitochondrial Ca2+ coupling, and/or the mitochondrial Ca2+ entry through the uniporter. Following a 16-week high-fat high-sucrose diet (HFHSD), mice developed cardiac insulin resistance, fibrosis, hypertrophy, lipid accumulation, and diastolic dysfunction when compared to standard diet. Ultrastructural and proteomic analyses of cardiac reticulum-mitochondria interface revealed tighter interactions not compatible with Ca2+ transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca2+ sensors were performed to measure Ca2+ fluxes in freshly isolated adult cardiomyocytes and to analyze the direct effects of in vivo type 2 diabetes on cardiomyocyte function. HFHSD resulted in a decreased IP3R-VDAC interaction and a reduced IP3-stimulated Ca2+ transfer to mitochondria, with no changes in reticular Ca2+ level, cytosolic Ca2+ transients, and mitochondrial Ca2+ uniporter function. Disruption of organelle Ca2+ exchange was associated with decreased mitochondrial bioenergetics and reduced cell contraction, which was rescued by an adenovirus-mediated expression of a reticulum-mitochondria linker. An 8-week diet reversal was able to restore cardiac insulin signaling, Ca2+ transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum-mitochondria Ca2+ miscoupling may play an early and reversible role in the development of diabetic cardiomyopathy by disrupting primarily the mitochondrial bioenergetics. A diet reversal, by counteracting the MAM-induced mitochondrial Ca2+ dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy.

Keywords:  Ca2+ flux; Diabetic cardiomyopathy; Metabolic syndrome disease; Mitochondria-associated membranes MAM; Protein database; Proteomic analysis of cardiac MAM proteome

DOI:  https://doi.org/10.1007/s00395-020-00835-7
Exp Gerontol. 2020 Nov 25. pii: S0531-5565(20)30519-2. [Epub ahead of print] 111171

Type-2 muscle fiber atrophy is associated with sarcopenia in elderly men with hip fracture.

Fabiana Tanganelli, Peter Meinke, Fabian Hofmeister, Stefanie Jarmusch, Lisa Baber, Stefan Mehaffey, Stefan Hintze, Uta Ferrari, Carl Neuerburg, Christian Kammerlander, Benedikt Schoser, Michael Drey.

  Sarcopenia is a common geriatric syndrome and can lead to falls and fragility fractures. It is associated with a decline of muscle fiber numbers and size. Muscle biopsies of the vastus lateralis muscle were taken from thirty-two patients with hip fracture (18 women and 14 men; mean age: 82.2 ± 6.2 years). Serial cross sections of skeletal muscle were labeled with myosin heavy chain slow (fiber type-1) and fast (fiber type-2) antibodies in order to measure the size, ratio and percentage of mixed fiber types. The presence of sarcopenia was defined according to the EWGSOP2 criteria by using BIA and handgrip strength measurement. Sarcopenia was identified in 5 patients (3 women and 2 men), probable-sarcopenia in 11 patients (4 women and 7 men). Significant differences in fiber diameter were found for fiber type-2 in men but not in women. Only 1-3% mixed fiber types were found in sarcopenic patients, indicating a final stage where reinnervation is not possible to occur anymore. Muscle fiber type-2 atrophy seems to be a histological marker for sarcopenia in men.

Keywords:  Hip fracture; Muscle histology; Sarcopenia; Type-2 muscle fiber atrophy

DOI:  https://doi.org/10.1016/j.exger.2020.111171