bims-misrem 2021-09-12 papers

Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2025932118. [Epub ahead of print]118(37):

Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy.

Mitochondria form a complex, interconnected reticulum that is maintained through coordination among biogenesis, dynamic fission, and fusion and mitophagy, which are initiated in response to various cues to maintain energetic homeostasis. These cellular events, which make up mitochondrial quality control, act with remarkable spatial precision, but what governs such spatial specificity is poorly understood. Herein, we demonstrate that specific isoforms of the cellular bioenergetic sensor, 5' AMP-activated protein kinase (AMPKα1/α2/β2/γ1), are localized on the outer mitochondrial membrane, referred to as mitoAMPK, in various tissues in mice and humans. Activation of mitoAMPK varies across the reticulum in response to energetic stress, and inhibition of mitoAMPK activity attenuates exercise-induced mitophagy in skeletal muscle in vivo. Discovery of a mitochondrial pool of AMPK and its local importance for mitochondrial quality control underscores the complexity of sensing cellular energetics in vivo that has implications for targeting mitochondrial energetics for disease treatment.

Keywords: AMPK; exercise; mitochondria; mitophagy; skeletal muscle

DOI: https://doi.org/10.1073/pnas.2025932118

J Appl Physiol (1985). 2021 Sep 09.

Acute erythropoietin injection increases muscle mitochondrial respiratory capacity in young men: A double-blinded randomized crossover trial.

Steen Larsen, Stine Dam Søndergård, Ronni Eg Sahl, Jacob Frandsen, Thomas Morville, Flemming Dela, Jorn Wulff Helge.

The aim was to investigate if acute recombinant human erythropoietin (rHuEPO) injection had an effect on mitochondrial function and if exercise would have an additive effect. Furthermore to investigate if in-vitro incubation with rHuEPO had an effect on muscle mitochondrial respiratory capacity. Eight healthy young men were recruited for this double blinded randomized placebo controlled crossover study. rHuEPO (400 IU/kg body weight) or saline injection was given intravenously, before an acute bout of exercise. Resting metabolic rate and fat oxidation were measured. Biopsies were obtained at baseline, 120 min after injection and right after the acute exercise bout. Mitochondrial function (mitochondrial respiration and H2O2 emission) was measured in permeabilized skeletal muscle using high-resolution respirometry and fluorometry. Specifik gene expression and enzyme activity were measured. Skeletal muscle mitochondrial respiratory capacity was measured with and without incubation with rHuEPO. Fat oxidation at rest increased after rHuEPO injection, but no difference was found in fat oxidation during exercise. Mitochondrial respiratory capacity was increased after rHuEPO injection when pyruvate was in the assay, which was not the case when saline was injected. No changes were seen in H2O2 emission after rHuEPO injection or acute exercise. Incubation of skeletal muscle fibers in-vitro with rHuEPO increased mitochondrial respiratory capacity. Acute rHuEPO injection increased mitochondrial respiratory capacity when pyruvate was used in the assay. No statistical difference was found in H2O2 emission capacity, although a numerical increase was seen after rHuEPO injection. In-vitro incubation of the skeletal muscle sample with rHuEPO increases mitochondrial respiratory capacity.

Keywords: EPO; H2O2 emission; exercise; human; mitochondrial biogenesis

DOI: https://doi.org/10.1152/japplphysiol.00995.2020

J Physiol. 2021 Sep 10.

Peripheral impairments of oxidative metabolism after a 10-day bed rest are upstream of mitochondrial respiration.

Lucrezia Zuccarelli, Giovanni Baldassarre, Benedetta Magnesa, Cristina Degano, Marina Comelli, Mladen Gasparini, Giorgio Manferdelli, Mauro Marzorati, Irene Mavelli, Andrea Pilotto, Simone Porcelli, Letizia Rasica, Boštjan Šimunič, Rado Pišot, Marco Narici, Bruno Grassi.

KEY POINTS: 10-day of horizontal bed rest impaired in vivo oxidative function during exercise. Microvascular impairments were identified by different methods. Mitochondrial mass and mitochondrial function (evaluated both in vivo and ex vivo) were unchanged or even improved (i.e., enhanced mitochondrial sensitivity to submaximal [ADP]). Resting muscle oxygen uptake was significantly lower following bed rest, suggesting that muscle catabolic processes induced by bed rest/inactivity are less energy-consuming than anabolic ones.
ABSTRACT: In order to identify peripheral biomarkers of impaired oxidative metabolism during exercise following a 10-day bed rest (BR), 10 males performed an incremental exercise (to determine peak pulmonary V̇O2 [V̇O2 p]) and moderate-intensity exercises, before (PRE) and after (POST) BR. Blood flow response was evaluated in the common femoral artery by Eco-Doppler during 1-min passive leg movements (PLM). The intramuscular matching between O2 delivery and O2 utilization was evaluated by near-infrared spectroscopy (NIRS). Mitochondrial respiration was evaluated ex vivo by high-resolution respirometry in isolated muscle fibers, and in vivo by NIRS by the evaluation of skeletal muscle V̇O2 (V̇O2 m) recovery kinetics. Resting V̇O2 m was estimated by NIRS. Peak V̇O2 p was lower in POST vs. PRE. The area under the blood flow vs. time curve during PLM was smaller (P = 0.03) in POST (274 ± 233 mL) vs. PRE (427 ± 291). An increased (P = 0.03) overshoot of muscle deoxygenation during a metabolic transition was identified in POST. Skeletal muscle citrate synthase activity was not different (P = 0.11) in POST (131 ± 16 nmol. min-1. mg-1 ) vs. PRE (138 ± 19). Maximal ADP-stimulated mitochondrial respiration (66 ± 18 pmol. s-1. mg-1 [POST] vs. 72 ± 14 [PRE], P = 0.41) was not affected by BR. Apparent Km for ADP sensitivity of mitochondrial respiration was reduced in POST vs. PRE (P = 0.04). The V̇O2 m recovery time-constant was not different (P = 0.79) in POST (22 ± 6 s) vs. PRE (22 ± 6). Resting V̇O2 m was reduced by 25% in POST vs. PRE (P = 0.006). Microvascular-endothelial function was impaired following a 10-day BR, whereas mitochondrial mass and function (both in vivo and ex vivo) were unaffected or slightly enhanced. This article is protected by copyright. All rights reserved.

Keywords: NIRS; PLM; bed rest; microgravity; mitochondrial respiration; oxidative metabolism; skeletal muscle

DOI: https://doi.org/10.1113/JP281800

Int J Mol Sci. 2021 Sep 06. pii: 9655. [Epub ahead of print]22(17):

ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria.

Christian Koch, Maya Schuldiner, Johannes M Herrmann.

Most mitochondrial proteins are synthesized in the cytosol and targeted to the mitochondrial surface in a post-translational manner. The surface of the endoplasmic reticulum (ER) plays an active role in this targeting reaction. ER-associated chaperones interact with certain mitochondrial membrane protein precursors and transfer them onto receptor proteins of the mitochondrial surface in a process termed ER-SURF. ATP-driven proteins in the membranes of mitochondria (Msp1, ATAD1) and the ER (Spf1, P5A-ATPase) serve as extractors for the removal of mislocalized proteins. If the re-routing to mitochondria fails, precursors can be degraded by ER or mitochondria-associated degradation (ERAD or MAD respectively) in a proteasome-mediated reaction. This review summarizes the current knowledge about the cooperation of the ER and mitochondria in the targeting and quality control of mitochondrial precursor proteins.

Keywords: ER-SURF; chaperones; contact sites; endoplasmic reticulum; membrane extraction; mitochondria; protein targeting

DOI: https://doi.org/10.3390/ijms22179655

FASEB J. 2021 Oct;35(10): e21867

Low lysophosphatidylcholine induces skeletal muscle myopathy that is aggravated by high-fat diet feeding.

Patrick J Ferrara, Anthony R P Verkerke, J Alan Maschek, Justin L Shahtout, Piyarat Siripoksup, Hiroaki Eshima, Jordan M Johnson, Jonathan J Petrocelli, Ziad S Mahmassani, Thomas D Green, Joseph M McClung, James E Cox, Micah J Drummond, Katsuhiko Funai.

Obesity alters skeletal muscle lipidome and promotes myopathy, but it is unknown whether aberrant muscle lipidome contributes to the reduction in skeletal muscle contractile force-generating capacity. Comprehensive lipidomic analyses of mouse skeletal muscle revealed a very strong positive correlation between the abundance of lysophosphatidylcholine (lyso-PC), a class of lipids that is known to be downregulated with obesity, with maximal tetanic force production. The level of lyso-PC is regulated primarily by lyso-PC acyltransferase 3 (LPCAT3), which acylates lyso-PC to form phosphatidylcholine. Tamoxifen-inducible skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) was sufficient to reduce muscle lyso-PC content in both standard chow diet- and high-fat diet (HFD)-fed conditions. Strikingly, the assessment of skeletal muscle force-generating capacity ex vivo revealed that muscles from LPCAT3-MKI mice were weaker regardless of diet. Defects in force production were more apparent in HFD-fed condition, where tetanic force production was 40% lower in muscles from LPCAT3-MKI compared to that of control mice. These observations were partly explained by reductions in the cross-sectional area in type IIa and IIx fibers, and signs of muscle edema in the absence of fibrosis. Future studies will pursue the mechanism by which LPCAT3 may alter protein turnover to promote myopathy.

Keywords: diabetes; lysophospholipid; myopathy; skeletal muscle

DOI: https://doi.org/10.1096/fj.202101104R