bims-misrem 2021-10-03 papers

J Cachexia Sarcopenia Muscle. 2021 Sep 29.

Mitochondrial aberrations during the progression of disuse atrophy differentially affect male and female mice.

Megan E Rosa-Caldwell, Seongkyun Lim, Wesley S Haynie, Jacob L Brown, David E Lee, Kirsten R Dunlap, Lisa T Jansen, Tyrone A Washington, Michael P Wiggs, Nicholas P Greene.

BACKGROUND: Disuse decreases muscle size and is predictive of mortality across multiple pathologies. Detriments to mitochondrial function are hypothesized to underlie disuse-induced muscle atrophy. Little data exist on early mechanisms contributing to onset of these pathologies, nor is it known how they differ between sexes. The purpose of this study was to examine differential and conserved responses to mitochondrial quality control in male and female mice during the development and progression of disuse-induced atrophy.
METHODS: One hundred C57BL/6J mice (50 male and 50 female) were hindlimb unloaded to induce disuse atrophy for 0 (con), 24, 48, 72, or 168 h. At designated time-points, extensor digitorum longus, gastrocnemius, and soleus muscles were collected for analysis of mitochondrial quality control markers.
RESULTS: One hundred sixty-eight hours of disuse resulted in ~25% lower oxidative muscle fibre CSA in both male (P = 0.003) and female (P = 0.02) mice without any differences due to disuse in glycolytic fibres. In male mice, 48 h of unloading was sufficient to result in ~67% greater mitochondrial oxidative stress as assessed by the reporter gene pMitoTimer compared with 0 h (P = 0.002), this mitochondrial stress preceded detectable muscle loss. However in female mice, mitochondrial oxidative stress did not occur until 168 h of disuse (~40% greater mitochondrial oxidative stress in 168 h compared with 0 h of disuse, P < 0.0001). Blunted oxidative stress in female mice appeared to coincide with greater inductions of autophagy and mitophagy in female mice (~3-fold greater BNIP3 and ~6-fold greater LC3II/I ratio P < 0.0001 and P = 0.038 respectively). Male mice overall had greater reactive oxygen species (ROS) production compared with female mice. Female mice had a greater induction of ROS within 24 h of disuse (~4-fold greater compared with 0 h, P < 0.0001); whereas male mice did not have greater ROS production until 168 h of disuse (~2-fold greater, P < 0.0001). Although all muscle types exhibited some alterations to mitochondrial quality control, such as increased markers of mitophagy and fission, the soleus muscle in both male and female mice exhibited consistent alterations to various markers of mitochondrial quality. Markers of mitochondrial translation were approximately 30-50% lower within 24 h of unloading in both male and female soleus muscle (P value ranges: <0.0001-0.03).
CONCLUSIONS: Disuse negatively affects mitochondria differentially between sexes during development of muscle wasting. Acutely, female mice may forgo muscle mass to maintain mitochondrial quality compared with male mice. These differences may contribute to divergent clinical manifestations of atrophy.

Keywords: Autophagy; Catabolism; Mitophagy; Muscle; Sex differences

DOI: https://doi.org/10.1002/jcsm.12809

J Cell Mol Med. 2021 Sep 26.

The interplay between mitochondria and store-operated Ca2+ entry: Emerging insights into cardiac diseases.

Jinliang Nan, Jiamin Li, Yinuo Lin, Muhammad Saif Ur Rahman, Zhengzheng Li, Lingjun Zhu.

Store-operated Ca2+ entry (SOCE) machinery, including Orai channels, TRPCs, and STIM1, is key to cellular calcium homeostasis. The following characteristics of mitochondria are involved in the physiological and pathological regulation of cells: mitochondria mediate calcium uptake through calcium uniporters; mitochondria are regulated by mitochondrial dynamic related proteins (OPA1, MFN1/2, and DRP1) and form mitochondrial networks through continuous fission and fusion; mitochondria supply NADH to the electron transport chain through the Krebs cycle to produce ATP; under stress, mitochondria will produce excessive reactive oxygen species to regulate mitochondria-endoplasmic reticulum interactions and the related signalling pathways. Both SOCE and mitochondria play critical roles in mediating cardiac hypertrophy, diabetic cardiomyopathy, and cardiac ischaemia-reperfusion injury. All the mitochondrial characteristics mentioned above are determinants of SOCE activity, and vice versa. Ca2+ signalling dictates the reciprocal regulation between mitochondria and SOCE under the specific pathological conditions of cardiomyocytes. The coupling of mitochondria and SOCE is essential for various pathophysiological processes in the heart. Herein, we review the research focussing on the reciprocal regulation between mitochondria and SOCE and provide potential interplay patterns in cardiac diseases.

Keywords: cardiac hypertrophy; diabetic cardiomyopathy; endoplasmic reticulum; ischaemia-reperfusion injury; mitochondria; store-operated Ca2+ entry

DOI: https://doi.org/10.1111/jcmm.16941

J Exp Biol. 2021 Sep 28. pii: jeb.242462. [Epub ahead of print]

A higher mitochondrial content is associated with greater oxidative damage, oxidative defenses, protein synthesis and ATP turnover in resting skeletal muscle.

Julie M Neurohr, Erik T Paulson, Stephen T Kinsey.

An unavoidable consequence of aerobic metabolism is the production of reactive oxygen species (ROS). Mitochondria have historically been considered the primary source of ROS, however, recent literature has highlighted the uncertainty in primary ROS production sites and it is unclear how variation in mitochondrial density influences ROS-induced damage and protein turnover. Fish skeletal muscle is comprised of distinct, highly aerobic red muscle and anaerobic white muscle, offering an excellent model system in which to evaluate the relationship of tissue aerobic capacity and ROS-induced damage under baseline conditions. The present study uses a suite of indices to better understand potential consequences of aerobic tissue capacity in red and white muscle of the pinfish, Lagodon rhomboides. Red muscle had a 7-fold greater mitochondrial volume density than white muscle, and more oxidative damage despite also having higher activities of the antioxidant enzymes superoxide dismutase and catalase. The dominant protein degradation system appears to be tissue dependent. Lysosomal degradation markers and autophagosome volume density were greater in white muscle, while ubiquitin expression and 20S proteasome activity were significantly greater in red muscle. However, ubiquitin ligase expression was significantly higher in white muscle. Red muscle had a more than two-fold greater rate of translation and total ATP turnover than white muscle, results that may be due in part to the higher mitochondrial density and the associated increase in oxidative damage. Together these results support the concept that an elevated aerobic capacity is associated with greater oxidative damage and higher costs of protein turnover.

Keywords: Autophagy; Oxidative stress; Protein turnover; Ubiquitin proteasome system

DOI: https://doi.org/10.1242/jeb.242462

FASEB J. 2021 Oct;35(10): e21891

The fasting-feeding metabolic transition regulates mitochondrial dynamics.

Mauricio Castro-Sepúlveda, Béatrice Morio, Mauro Tuñón-Suárez, Sebastian Jannas-Vela, Francisco Díaz-Castro, Jennifer Rieusset, Hermann Zbinden-Foncea.

In humans, insulin resistance has been linked to an impaired metabolic transition from fasting to feeding (metabolic flexibility; MetFlex). Previous studies suggest that mitochondrial dynamics response is a putative determinant of MetFlex; however, this has not been studied in humans. Thus, the aim of this study was to investigate the mitochondrial dynamics response in the metabolic transition from fasting to feeding in human peripheral blood mononuclear cells (PBMCs). Six male subjects fasted for 16 h (fasting), immediately after which they consumed a 75-g oral glucose load (glucose). In both fasting and glucose conditions, blood samples were taken to obtain PBMCs. Mitochondrial dynamics were assessed by electron microscopy images. We exposed in vitro acetoacetate-treated PBMCs to the specific IP3R inhibitor Xestospongin B (XeB) to reduce IP3R-mediated mitochondrial Ca2+ accumulation. This allowed us to evaluate the role of ER-mitochondria Ca2+ exchange in the mitochondrial dynamic response to substrate availability. To determine whether PBMCs could be used in obesity context (low MetFlex), we measured mitochondrial dynamics in mouse spleen-derived lymphocytes from WT and ob/ob mice. We demonstrated that the transition from fasting to feeding reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs. In addition, we demonstrated that IP3R activity is key in the mitochondrial dynamics response when PBMCs are treated with a fasting-substrate in vitro. In murine mononuclear-cells, we confirmed that mitochondria-ER interactions are regulated in the fasted-fed transition and we further highlight mitochondria-ER miscommunication in PBMCs of diabetic mice. In conclusion, our results demonstrate that the fasting/feeding transition reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs, and that IP3R activity may potentially play a central role.

Keywords: fasting; mitochondria-ER interaction; mitochondrial cristae; mitochondrial fusion; mitochondrial morphology; obesity

DOI: https://doi.org/10.1096/fj.202100929R