bims-misrem 2021-08-15 papers

bims-misrem

Biomed News

on Mitochondria and sarcoplasmic reticulum in muscle mass

Issue of 2021–08–15
seven papers selected by
Rafael Antonio Casuso Pérez, University of Granada

Endurance training alleviates MCP-1 and TERRA accumulation at old age in human skeletal muscle.
PERM1 interacts with the MICOS-MIB complex to connect the mitochondria and sarcolemma via ankyrin B.
Acetyl-CoA-driven respiration in frozen muscle contributes to the diagnosis of mitochondrial disease.
Effects of long-term immobilisation on endomysium of the soleus muscle in humans.
Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam KO mouse model.
Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy.
Endurance training-induced increase in muscle oxidative capacity without loss of muscle mass in younger and older resistance-trained men.

Exp Gerontol. 2021 Aug 06. pii: S0531-5565(21)00292-8. [Epub ahead of print] 111510

Endurance training alleviates MCP-1 and TERRA accumulation at old age in human skeletal muscle.

Estelle Balan, Aurélie Diman, Amandine Everard, Henri Nielens, Anabelle Decottignies, Louise Deldicque.

  Both oxidative stress and telomere transcription are up-regulated by acute endurance exercise in human skeletal muscle. Whether and how life-long exercise training influences the antioxidant system response at transcriptional level and TERRA expression is unknown, especially during aging. Response to acute endurance exercise was investigated in muscle biopsies of 3 male subjects after 45 min of cycling. MCP-1 and SOD1 mRNA levels increased up to, 15-fold and 63%, respectively, after the cycling session while the mRNA levels of SOD2 were downregulated by 25%. The effects of chronic endurance exercise and aging were tested in the blood and muscle of 34 male subjects divided into four groups: young (YU) or old (OU) untrained, young (YT) or old (OT) trained cyclists. Long-term endurance training limited the age-dependent elevation in SOD1 (OT vs OU, -26%, P = 0.03) and the decline in SOD2 mRNA levels (OU vs YU, -41%, P = 0.04). A high endurance training status alleviated the age-related increase in the aging biological marker MCP-1 in plasma (OU vs YU, +48%, P = 0.005). Similar results were observed for telomeric transcription as the age-associated increase in 16p TERRA levels (OU vs YU, +39%, P = 0.001) was counteracted by a high endurance training status (OT vs OU, -63%, P = 0.0005). In conclusion, as MCP-1, we propose that the age-related TERRA accumulation might represent a novel biological marker of aging. Those aging-related increase expression might be alleviated by a high endurance training status. Whether those biological markers of aging are linked to an elevation of oxidative stress is still an open question. Therefore, whether the positive adaptations provided by endurance training indeed reduce oxidative stress, including at telomeres, and whether TERRA plays any role in this, need to be further investigated.

Keywords:  Exercise; Inflammation; Oxidative stress; Physical activity; Telomere

DOI:  https://doi.org/10.1016/j.exger.2021.111510
Nat Commun. 2021 08 12. 12(1): 4900

PERM1 interacts with the MICOS-MIB complex to connect the mitochondria and sarcolemma via ankyrin B.

Theresa Bock, Clara Türk, Sriram Aravamudhan, Lena Keufgens, Wilhelm Bloch, Dieu Hien Rozsivalova, Vanina Romanello, Leonardo Nogara, Bert Blaauw, Aleksandra Trifunovic, Thomas Braun, Marcus Krüger.

Skeletal muscle subsarcolemmal mitochondria (SSM) and intermyofibrillar mitochondria subpopulations have distinct metabolic activity and sensitivity, though the mechanisms that localize SSM to peripheral areas of muscle fibers are poorly understood. A protein interaction study and complexome profiling identifies PERM1 interacts with the MICOS-MIB complex. Ablation of Perm1 in mice reduces muscle force, decreases mitochondrial membrane potential and complex I activity, and reduces the numbers of SSM in skeletal muscle. We demonstrate PERM1 interacts with the intracellular adaptor protein ankyrin B (ANKB) that connects the cytoskeleton to the plasma membrane. Moreover, we identify a C-terminal transmembrane helix that anchors PERM1 into the outer mitochondrial membrane. We conclude PERM1 functions in the MICOS-MIB complex and acts as an adapter to connect the mitochondria with the sarcolemma via ANKB.

DOI: https://doi.org/10.1038/s41467-021-25185-3
Eur J Clin Invest. 2021 Sep;51(9): e13574

Acetyl-CoA-driven respiration in frozen muscle contributes to the diagnosis of mitochondrial disease.

Felippe Henrique Zuccolotto-Dos-Reis, Silvia Helena Andrião Escarso, Jackeline Souza Araujo, Enilza Maria Espreafico, Luciane Carla Alberici, Claudia Ferreira da Rosa Sobreira.

   BACKGROUND: Freezing human biopsies is common in clinical practice for storage. However, this technique disrupts mitochondrial membranes, hampering further analyses of respiratory function. To contribute to laboratorial diagnosis of mitochondrial diseases, this study sought to develop a respirometry approach using O2k (Oroboros Ins.) to measure the whole electron transport chain (ETC) activity in homogenates of frozen skeletal muscle biopsies.
PATIENTS AND METHODS: We enrolled 16 patients submitted to muscle biopsy in the process of routine diagnostic investigation: four with mitochondrial disease and severe mitochondrial dysfunction; seven with exercise intolerance and multiple deletions of mitochondrial DNA, presenting mild to moderate mitochondrial dysfunction; five without mitochondrial disease, as controls. Whole homogenates of muscle fragments were prepared using grinder-type equipment. O2 consumption rates were normalized using citrate synthase activity.
RESULTS: Transmission electron microscopy confirmed mitochondrial membrane discontinuation, indicating increased permeability of mitochondrial membranes in homogenates from frozen biopsies. O2 consumption rates in the presence of acetyl-CoA lead to maximum respiratory rates sensitive to rotenone, malonate and antimycin. This protocol of acetyl-CoA-driven respiration (ACoAR), applied in whole homogenates of frozen muscle, was sensitive enough to identify ETC abnormality, even in patients with mild to moderate mitochondrial dysfunction. We demonstrated adequate repeatability of ACoAR and found significant correlation between O2 consumption rates and enzyme activity assays of individual ETC complexes.
CONCLUSIONS: We present preliminary data on a simple, low cost and reliable procedure to measure respiratory function in whole homogenates of frozen skeletal muscle biopsies, contributing to diagnosis of mitochondrial diseases in humans.

Keywords:  acetyl-CoA-driven respiration; electron transport chain; frozen skeletal muscle biopsy; high-resolution respirometry; mitochondrial diseases; oxygen consumption rate

DOI:  https://doi.org/10.1111/eci.13574
Exp Physiol. 2021 Aug 13.

Effects of long-term immobilisation on endomysium of the soleus muscle in humans.

Georgina K Thot, Carolin Berwanger, Edwin Mulder, Jessica K Lee, Yannick Lichterfeld, Bergita Ganse, Ifigeneia Giakoumaki, Hans Degens, Ibrahim Duran, Eckhard Schönau, Christoph S Clemen, Bent Brachvogel, Jörn Rittweger.

   NEW FINDINGS: What is the central question of this study? While muscle fibre atrophy in response to immobilisation has been extensively examined, intramuscular connective tissue, particularly endomysium, have been largely neglected. We investigated whether endomysium content of the soleus muscle increases during bed rest. What is the main finding and its importance? Analysing muscle biopsy data from a 60-day bed rest study, we found that absolute endomysium content did not change, and previous studies reporting an increase are explicable by muscle fibre atrophy. It must be expected that even a relative connective tissue accumulation will lead to an increase in muscle stiffness.
ABSTRACT: Muscle fibres atrophy during conditions of disuse. Whilst animal data suggest an increase in endomysium content with disuse, that information is not available in humans. We hypothesised that endomysium content increases during immobilisation. To test this hypothesis, biopsy samples of the soleus muscle obtained from 21 volunteers who underwent 60-days of bed rest were analysed using immunofluorescence-labelled laminin γ-1 to delineate individual muscles fibres as well as the endomysium space. The endomysium-to-fibre-area ratio (EFAr, in %) was assessed as a measure related to stiffness, and the endomysium-to-fibre-number ratio (EFNr) was calculated to determine whether any increase in EFAr was absolute, or could be attributed to muscle fibre shrinkage. As expected, we found muscle fibre atrophy (p = 0.0031) that amounted to shrinkage by 16.6% (SD 28.2%) on day 55 of bed rest. ENAr increased on day 55 of bed rest (p < 0.001). However, when analysing EFNr, no effect of bed rest was found (p = 0.62). These results demonstrate that an increase in EFAr is likely a direct effect of muscle fibre atrophy. Based on the assumption that the total number of muscle fibres remains unchanged during 55 days of bed rest, this implies that the absolute amount of connective tissue in the soleus muscle remained unchanged. The increased relative endomysium content, however, could be functionally related to an increase in muscle stiffness. This article is protected by copyright. All rights reserved.

Keywords:  connective tissue; endomysium; immobilisation; muscle atrophy

DOI:  https://doi.org/10.1113/EP089734
Dis Model Mech. 2021 Aug 11. pii: dmm.048981. [Epub ahead of print]

Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam KO mouse model.

Benjamin Chatel, Sylvie Ducreux, Zeina Harhous, Nadia Bendridi, Isabelle Varlet, Augustin C Ogier, Monique Bernard, Julien Gondin, Jennifer Rieusset, Håkan Westerblad, David Bendahan, Charlotte Gineste.

  Mitochondrial diseases are genetic disorders leading to an impaired mitochondrial function and resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, the fast-twitch skeletal muscle-specific Tfam deletion (Tfam KO) leads to deficit in the respiratory chain activity, severe muscle weakness and early death. Here, we performed a time-course study of mitochondrial and muscular dysfunctions in 11 and 14 weeks Tfam KO mice, i.e., before and when mice are about to enter the terminal stage, respectively. While force in the unfatigued state was reduced in Tfam KO mice as compared to control littermates (WT) only at 14 weeks, during repeated submaximal contractions fatigue was faster at both ages. During fatiguing stimulation, total phosphocreatine breakdown was larger in Tfam KO muscle than in WT muscle at both ages whereas phosphocreatine consumption was faster only at 14 weeks. In conclusion, the Tfam KO mouse model represents a reliable model of lethal mitochondrial myopathy where impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death.

Keywords:  Energy metabolism; Exercise intolerance; Mitochondrial myopathy; Muscle fatigue; Muscle weakness

DOI:  https://doi.org/10.1242/dmm.048981
Cell Death Differ. 2021 Aug 13.

Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy.

Marta Zaninello, Konstantinos Palikaras, Aggeliki Sotiriou, Nektarios Tavernarakis, Luca Scorrano.

Mitochondrial dysfunction and mitophagy are often hallmarks of neurodegenerative diseases such as autosomal dominant optic atrophy (ADOA) caused by mutations in the key mitochondrial dynamics protein optic atrophy 1 (Opa1). However, the second messengers linking mitochondrial dysfunction to initiation of mitophagy remain poorly characterized. Here, we show in mammalian and nematode neurons that Opa1 mutations trigger Ca2+-dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells and Caenorhabditis elegans motor neurons lead to mitochondrial dysfunction, increased cytosolic Ca2+ levels, and decreased axonal mitochondrial density. Chelation of Ca2+ restores mitochondrial density in neuronal processes, neuronal function, and viability. Mechanistically, sustained Ca2+ levels activate calcineurin and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density. Our data reveal that mitophagy in ADOA depends on Ca2+-calcineurin-AMPK signaling cascade.

DOI: https://doi.org/10.1038/s41418-021-00847-3
Eur J Appl Physiol. 2021 Aug 14.

Endurance training-induced increase in muscle oxidative capacity without loss of muscle mass in younger and older resistance-trained men.

Paul William Hendrickse, Tomas Venckunas, Justinas Platkevicius, Ramutis Kairaitis, Sigitas Kamandulis, Audrius Snieckus, Arvydas Stasiulis, Jolanta Vitkiene, Andrejus Subocius, Hans Degens.

  While concurrent training is regularly used in older populations, the inverse relationship between fibre size and oxidative capacity suggests that endurance training in resistance-trained individuals may result in some loss of resistance training-induced gains in muscle mass, which may be more pronounced in older people. We investigated the impact of superimposed endurance training in younger (28.5 ± 4.8 years; n = 8) and older (67.5 ± 5.5 years; n = 7) highly resistance-trained men. Participants underwent a 10-week endurance cycling training programme consisting of five 6-min intervals at 75% max heart rate (HRmax) separated by 4-min intervals at 90% HRmax. The anatomical cross-sectional area (ACSA) of the thigh muscles, as determined with MRI, was 24% smaller in older compared to younger participants (p < 0.001). Although maximal oxygen consumption (VO2max) was also lower in the older group (p < 0.001), VO2max per kg body mass did not differ significantly between younger and older participants. Histological analyses of biopsies of the m. vastus lateralis showed that endurance training induced an increase in succinate dehydrogenase activity in both younger and older participants (p ≤ 0.043), and an increase in the number of capillaries around type I fibres (p = 0.017). The superimposed endurance training did not induce a significant decrease in thigh ACSA, fibre cross-sectional area, or knee extensor maximum voluntary isometric force. These observations indicate that adding endurance training to resistance training can lead to positive endurance-related adaptations without negative consequences for muscle size and strength in older and younger resistance-trained people.

Keywords:  Capillarisation; Muscle size

DOI:  https://doi.org/10.1007/s00421-021-04768-4