bims-misrem 2021-06-13 papers

Med Sci Sports Exerc. 2021 Jun 07.

Skeletal Muscle Mitochondrial Function following a 100-km Ultramarathon: A Case Study in Monozygotic Twins.

Erik D Marchant, Nathan D Marchant, Robert D Hyldahl, Jayson R Gifford, Michael W Smith, Chad R Hancock.

PURPOSE: Very little research has investigated the effects of ultra-endurance exercise on the bioenergetic status of muscle. The primary objective of this case study was to characterize the changes that occur in skeletal muscle mitochondria in response to a 100-km ultramarathon in monozygotic twins. A second objective was to determine whether mitochondrial function is altered by consuming a periodized low-carbohydrate, high-fat diet (LCHFD) during training compared to a high-carbohydrate diet.
METHODS: One pair of male monozygotic twins ran 100 km on treadmills following 4 weeks of training on either a high carbohydrate or periodized LCHFD. Muscle biopsies were collected 4 weeks prior to the run, as well as 4- and 52-hours post-run. Blood draws were also performed immediately before, as well as 4- and 52-hours post-run.
RESULTS: Four hours post-run, respiratory capacity, citrate synthase activity and mitochondrial complex protein content were decreased. Two days later, both twins showed signs of rapid recovery in several of these measures. Furthermore, blood levels of creatine phosphokinase, C-reactive protein, and aspartate transaminase were elevated 4 hours after the run, but partially recovered two days later.
CONCLUSION: Although there were some differences between the twins, the primary finding is that there is significant mitochondrial impairment induced by running 100 km, which rapidly recovers within 2 days. These results provide ample rationale for future investigations of the effects of ultra-endurance activity on mitochondrial function.

DOI: https://doi.org/10.1249/MSS.0000000000002715

Adv Protein Chem Struct Biol. 2021 ;pii: S1876-1623(21)00025-0. [Epub ahead of print]126 307-343

Apoptotic signals at the endoplasmic reticulum-mitochondria interface.

Flavia Giamogante, Elena Poggio, Lucia Barazzuol, Alberto Covallero, Tito Calì.

The maintenance of cellular homeostasis involves the participation of multiple organelles, such as the endoplasmic reticulum (ER) and mitochondria. Specifically, ER plays a key role in calcium (Ca2+) storage, lipid synthesis, protein folding, and assembly, while mitochondria are the "energy factories" and provide energy to drive intracellular processes. Hence, alteration in ER or mitochondrial homeostasis has detrimental effects on cell survival, being linked to the triggering of apoptosis, a programmed form of cell death. Besides, ER stress conditions affect mitochondria functionality and vice-versa, as ER and mitochondria communicate via mitochondria-associated ER membranes (MAMs) to carry out a number of fundamental cellular functions. It is not surprising, thus, that also MAMs perturbations are involved in the regulation of apoptosis. This chapter intends to accurately discuss the involvement of MAMs in apoptosis, highlighting their crucial role in controlling this delicate cellular process.

Keywords: Apoptosis; Bioenergetics; Calcium signaling; ER-mitochondria contact sites; MAMs; Organelle tethering

DOI: https://doi.org/10.1016/bs.apcsb.2021.02.007

J Appl Physiol (1985). 2021 Jun 10.

Short term intensified training temporarily impairs mitochondrial respiratory capacity in elite endurance athletes.

Daniele A Cardinale, Kasper D Gejl, Kristine Grøsfjeld Petersen, Joachim Nielsen, Niels Ørtenblad, Filip J Larsen.

AIM: The maintenance of healthy and functional mitochondria is the result of a complex mitochondrial turnover and herein quality-control program which includes both mitochondrial biogenesis and autophagy of mitochondria. The aim of this study was to examine the effect of an intensified training load on skeletal muscle mitochondrial quality control in relation to changes in mitochondrial oxidative capacity, maximal oxygen consumption and performance in highly trained endurance athletes.
METHODS: 27 elite endurance athletes performed high intensity interval exercise followed by moderate intensity continuous exercise 3 days per week for 4 weeks in addition to their usual volume of training. Mitochondrial oxidative capacity, abundance of mitochondrial proteins, markers of autophagy and antioxidant capacity of skeletal muscle were assessed in skeletal muscle biopsies before and after the intensified training period.
RESULTS: The intensified training period increased several autophagy markers suggesting an increased turnover of mitochondrial and cytosolic proteins. In permeabilized muscle fibers, mitochondrial respiration was ~20 % lower after training although some markers of mitochondrial density increased by 5-50%, indicative of a reduced mitochondrial quality by the intensified training intervention. The antioxidative proteins UCP3, ANT1, and SOD2 were increased after training, whereas we found an inactivation of aconitase. In agreement with the lower aconitase activity, the amount of mitochondrial LON protease that selectively degrades oxidized aconitase, was doubled.
CONCLUSION: Together, this suggests that mitochondrial respiratory function is impaired during the initial recovery from a period of intensified endurance training while mitochondrial quality control is slightly activated in highly trained skeletal muscle.

Keywords: athletes; endurance; mitochondrial oxidative capacity; mitochondrial quality-control; mitophagy

DOI: https://doi.org/10.1152/japplphysiol.00829.2020

Aging Cell. 2021 Jun 07. e13408

Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan.

Tara R Richman, Judith A Ermer, Stefan J Siira, Irina Kuznetsova, Christopher A Brosnan, Giulia Rossetti, Jessica Baker, Kara L Perks, Henrietta Cserne Szappanos, Helena M Viola, Nicola Gray, Mark Larance, Livia C Hool, Steven Zuryn, Oliver Rackham, Aleksandra Filipovska.

Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error-prone (Mrps12ep / ep ) or hyper-accurate (Mrps12ha / ha ) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, Mrps12ep / ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha / ha mice protected the liver from a high-fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. These findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues. We show trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes due to commonly encountered stressful environmental conditions or aging.

Keywords: ageing; metabolism; mitochondria; protein synthesis

DOI: https://doi.org/10.1111/acel.13408

EMBO Rep. 2021 Jun 04. 22(6): e51323

Phospholipid transfer function of PTPIP51 at mitochondria-associated ER membranes.

Hyun Ku Yeo, Tae Hyun Park, Hee Yeon Kim, Hyonchol Jang, Jueun Lee, Geum-Sook Hwang, Seong Eon Ryu, Si Hoon Park, Hyun Kyu Song, Hyun Seung Ban, Hye-Jin Yoon, Byung Il Lee.

In eukaryotic cells, mitochondria are closely tethered to the endoplasmic reticulum (ER) at sites called mitochondria-associated ER membranes (MAMs). Ca2+ ion and phospholipid transfer occurs at MAMs to support diverse cellular functions. Unlike those in yeast, the protein complexes involved in phospholipid transfer at MAMs in humans have not been identified. Here, we determine the crystal structure of the tetratricopeptide repeat domain of PTPIP51 (PTPIP51_TPR), a mitochondrial protein that interacts with the ER-anchored VAPB protein at MAMs. The structure of PTPIP51_TPR shows an archetypal TPR fold, and an electron density map corresponding to an unidentified lipid-like molecule probably derived from the protein expression host is found in the structure. We reveal functions of PTPIP51 in phospholipid binding/transfer, particularly of phosphatidic acid, in vitro. Depletion of PTPIP51 in cells reduces the mitochondrial cardiolipin level. Additionally, we confirm that the PTPIP51-VAPB interaction is mediated by the FFAT-like motif of PTPIP51 and the MSP domain of VAPB. Our findings suggest that PTPIP51 is a phospholipid transfer protein with a MAM-tethering function.

Keywords: MAM; PTPIP51; endoplasmic reticulum; mitochondria; phospholipid

DOI: https://doi.org/10.15252/embr.202051323

J Physiol. 2021 Jun 09.

Impaired skeletal muscle fatigue resistance during cardiac hypertrophy is prevented by functional overload- or exercise-induced functional capillarity.

Peter G Tickle, Paul W Hendrickse, Andrew Weightman, M Hakam Nazir, Hans Degens, Stuart Egginton.

KEY POINTS: Capillary rarefaction is hypothesised to contribute to impaired exercise tolerance in cardiovascular disease, but it remains a poorly exploited therapeutic target for improving skeletal muscle performance. Using an abdominal aortic coarctation rat model of compensatory cardiac hypertrophy, we determine the efficacy of aerobic exercise for the prevention of, and mechanical overload for restoration of hind limb muscle fatigue resistance and microvascular impairment in the early stages of heart disease. Impaired muscle fatigue resistance was found after development of cardiac hypertrophy, but this impairment was prevented by low intensity aerobic exercise and recovered after mechanical stretch due to muscle overload. Changes in muscle fatigue resistance were closely related to functional (i.e. perfused) microvascular density, independent of arterial blood flow, emphasising the critical importance of optimal capillary diffusion for skeletal muscle function. Pro-angiogenic therapies are an important tool for improving skeletal muscle function in the incipient stages of heart disease.
ABSTRACT: Microvascular rarefaction may contribute to declining skeletal muscle performance in cardiac and vascular diseases. It remains uncertain to what extent microvascular rarefaction occurs in the earliest stages of these conditions, if impaired blood flow is an aggravating factor and whether angiogenesis restores muscle performance. To investigate this, the effects of aerobic exercise (voluntary wheel running) and functional muscle overload on the performance, femoral blood flow (FBF) and microvascular perfusion of the extensor digitorum longus (EDL) were determined in a chronic rat model of compensatory cardiac hypertrophy (CCH, induced by surgically imposed abdominal aortic coarctation). CCH was associated with hypertension (P = 0.001 vs. control) and increased relative heart mass (P<0.001). Immediately upon placing the aortic band (i.e. before development of CCH), post fatigue test FBF was reduced (P<0.003), coinciding with attenuated fatigue resistance (P = 0.039) indicating an acute arterial perfusion constraint on muscle performance. While FBF was normalised during CCH in chronic groups (P>0.05) fatigue resistance remained reduced (P = 0.039) and was associated with reduced (P = 0.009) functional capillarity after development of CCH without intervention, indicating a microvascular limitation to muscle performance. Normalisation of functional capillarity after aerobic exercise (P = 0.065) and overload (P = 0.329) in CCH coincided with restoration to control levels of muscle fatigue resistance (P>0.999), although overload-induced EDL hypertrophy (P = 0.027) and wheel running velocity and duration (both P<0.05) were attenuated after aortic banding. These data show that reductions in skeletal muscle performance during CCH can be countered by improving functional capillarity, providing a therapeutic target to improve skeletal muscle function in chronic diseases. This article is protected by copyright. All rights reserved.

Keywords: blood flow; cardiac hypertrophy; fatigue; microcirculation; skeletal muscle

DOI: https://doi.org/10.1113/JP281377

Metabolism. 2021 Jun 03. pii: S0026-0495(21)00103-7. [Epub ahead of print] 154803

Lipids activate skeletal muscle mitochondrial fission and quality control networks to induce insulin resistance in humans.

Christopher L Axelrod, Ciaran E Fealy, Melissa L Erickson, Gangarao Davuluri, Hisashi Fujioka, Wagner S Dantas, Emily Huang, Kathryn Pergola, Jacob T Mey, William T King, Anny Mulya, Daniel Hsia, Bartolome Burguera, Bernard Tandler, Charles L Hoppel, John P Kirwan.

BACKGROUND AND AIMS: A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial.
METHODS: 19 healthy adults (age:28.4 ± 1.7 years; BMI:22.7 ± 0.3 kg/m2) received an overnight intravenous infusion of lipid (20% Intralipid) or saline followed by a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity using a randomized crossover design. Skeletal muscle biopsies were obtained after the overnight lipid infusion to evaluate activation of mitochondrial dynamics proteins, ex-vivo mitochondrial membrane potential, ex-vivo oxidative phosphorylation and electron transfer capacity, and mitochondrial ultrastructure.
RESULTS: Overnight lipid infusion increased dynamin related protein 1 (DRP1) phosphorylation at serine 616 and PTEN-induced kinase 1 (PINK1) expression (P = 0.003 and P = 0.008, respectively) in skeletal muscle while reducing mitochondrial membrane potential (P = 0.042). The lipid infusion also increased mitochondrial-associated lipid droplet formation (P = 0.011), the number of dilated cristae, and the presence of autophagic vesicles without altering mitochondrial number or respiratory capacity. Additionally, lipid infusion suppressed peripheral glucose disposal (P = 0.004) and hepatic insulin sensitivity (P = 0.014).
CONCLUSIONS: These findings indicate that activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. Targeting mitochondrial dynamics and quality control represents a promising new pharmacological approach for treating insulin resistance and type 2 diabetes.
CLINICAL TRIAL REGISTRATION: NCT02697201, ClinicalTrials.gov.

DOI: https://doi.org/10.1016/j.metabol.2021.154803