bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2021‒03‒14
eight papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Cell Rep. 2021 Mar 09. pii: S2211-1247(21)00141-8. [Epub ahead of print]34(10): 108827
      Calcium transfer from the endoplasmic reticulum (ER) to mitochondria is a critical contributor to apoptosis. B cell lymphoma 2 (BCL-2) ovarian killer (BOK) localizes to the ER and binds the inositol 1,4,5-trisphosophate receptor (IP3R). Here, we show that BOK is necessary for baseline mitochondrial calcium levels and stimulus-induced calcium transfer from the ER to the mitochondria. Murine embryonic fibroblasts deficient for BOK have decreased proximity of the ER to the mitochondria and altered protein composition of mitochondria-associated membranes (MAMs), which form essential calcium microdomains. Rescue of the ER-mitochondrial juxtaposition with drug-inducible interorganelle linkers reveals a kinetic disruption, which when overcome in Bok-/- cells is still insufficient to rescue thapsigargin-induced calcium transfer and apoptosis. Likewise, a BOK mutant unable to interact with IP3R restores ER-mitochondrial proximity, but not ER-mitochondrial calcium transfer, MAM protein composition, or apoptosis. This work identifies the dynamic coordination of ER-mitochondrial contact by BOK as an important control point for apoptosis.
    Keywords:  BCL-2 family; BOK; IP3R; MAMs; MERCs; apoptosis; calcium; endoplasmic reticulum; mitochondria-ER contact sites; mitochondria-associated membranes
  2. Life Sci. 2021 Mar 03. pii: S0024-3205(21)00281-2. [Epub ahead of print]273 119296
      AIMS: Skeletal muscle mass and strength are reduced in asthma and contribute to compromised functional capacity in asthmatic patients. However, an effective pharmacological intervention remains elusive, partly because molecular mechanisms dictating muscle decline in asthma are not known.MATERIALS: We investigated the potential contribution(s) of skeletal muscle sarcoplasmic reticulum Ca2+ ATPase (SERCA) to muscle atrophy and weakness in asthmatic patients. Quadriceps muscle biopsies were taken from 58 to 72 years old male patients with mild and advanced asthma and the SERCA activity was analyzed in association with cellular redox environment and myonuclear domain (MND) size.
    KEY FINDINGS: Maximal SERCA activity was reduced in skeletal muscles of mild and advanced asthmatics and was associated with reduced expression of SERCA2 protein and upregulation of sarcolipin, a SERCA inhibitory lipoprotein. We also found downregulation of Ca2+ release protein calstabin and upregulation of Ca2+ buffer, calsequestrin in skeletal muscles of asthmatic patients. The atrophic single muscle fibers had smaller cytoplasmic domains per myonucleus possibly indicating the reduced transcriptional reserves of individual myonuclei. Plasma periostin and CAF22 levels were significantly elevated in asthmatic patients and showed a strong correlation with hand-grip strength. These changes were accompanied by substantially elevated markers of global oxidative stress including lipid peroxidation and mitochondrial ROS production.
    CONCLUSION: Taken together, our data suggest that muscle weakness and atrophy in asthma is in part driven by SERCA dysfunction and oxidative stress. The data propose SERCA dysfunction as a therapeutic intervention to address muscle decline in asthma.
    Keywords:  Asthma; Biomarkers; Oxidative stress; SERCA dysfunction; Skeletal muscle
  3. Trends Cell Biol. 2021 Mar 04. pii: S0962-8924(21)00028-3. [Epub ahead of print]
      Organelles cooperate with each other to control cellular homeostasis and cell functions by forming close connections through membrane contact sites. Important contacts are present between the endoplasmic reticulum (ER), the main intracellular Ca2+-storage organelle, and the mitochondria, the organelle responsible not only for the majority of cellular ATP production but also for switching on cell death processes. Several Ca2+-transport systems focalize at these contact sites, thereby enabling the efficient transmission of Ca2+ signals from the ER toward mitochondria. This provides tight control of mitochondrial functions at the microdomain level. Here, we discuss how ER-mitochondrial Ca2+ transfers support cell function and how their dysregulation underlies, drives, or contributes to pathogenesis and pathophysiology, with a major focus on cancer and neurodegeneration but also with attention to other diseases such as diabetes and rare genetic diseases.
    Keywords:  Ca(2+) signaling; MAMs; cancer; contact sites; genetic diseases; neurodegeneration
  4. FASEB J. 2021 Apr;35(4): e21459
      Chronic muscle loading (overload) induces skeletal muscles to undergo hypertrophy and to increase glucose uptake. Although AMP-activated protein kinase (AMPK) reportedly serves as a negative regulator of hypertrophy and a positive regulator of glucose uptake, its role in overload-induced skeletal muscle hypertrophy and glucose uptake is unclear. This study aimed to determine whether AMPK regulates overload-induced hypertrophy and glucose uptake in skeletal muscles. To this end, skeletal muscle overload was induced through unilateral synergist ablations in wild-type (WT) and transgenic mice, expressing the dominant-negative mutation of AMPK (AMPK-DN). After 14 days, parameters, including muscle fiber cross-sectional area (CSA), glycogen level, and in vivo [3 H]-2-deoxy-D-glucose uptake, were assessed. No significant difference was observed in body weight or blood glucose level between the WT and AMPK-DN mice. However, the 14-day muscle overload activated the AMPK pathway in WT mice skeletal muscle, whereas this response was impaired in the AMPK-DN mice. Despite a normal CSA gain in each fiber type, the AMPK-DN mice demonstrated a significant impairment of overload-induced muscle glucose uptake and glycogenesis, compared to WT mice. Moreover, 14-day overload-induced changes in GLUT4 and HKII expression levels were reduced in AMPK-DN mice, compared to WT mice. This study demonstrated that AMPK activation is indispensable for overload-induced muscle glucose uptake and glycogenesis; however, it is dispensable for the induction of hypertrophy in AMPK-DN mice. Furthermore, the AMPK/GLUT4 and HKII axes may regulate overload-induced muscle glucose uptake and glycogenesis.
    Keywords:  AMP-activated protein kinase; functional overload; glucose uptake; hypertrophy; skeletal muscle
  5. Semin Cell Dev Biol. 2021 Mar 08. pii: S1084-9521(21)00026-4. [Epub ahead of print]
      The endoplasmic reticulum (ER) and mitochondria connect at multiple contact sites to form a unique cellular compartment, termed the 'mitochondria-associated ER membranes' (MAMs). MAMs are hubs for signalling pathways that regulate cellular homeostasis and survival, metabolism, and sensitivity to apoptosis. MAMs are therefore involved in vital cellular functions, but they are dysregulated in several human diseases. Whilst MAM dysfunction is increasingly implicated in the pathogenesis of neurodegenerative diseases, its role in amyotrophic lateral sclerosis (ALS) is poorly understood. However, in ALS both ER and mitochondrial dysfunction are well documented pathophysiological events. Moreover, alterations to lipid metabolism in neurons regulate processes linked to neurodegenerative diseases, and a link between lipid metabolism dysfunction and ALS has also been proposed. In this review we discuss the structural and functional relevance of MAMs in ALS and how targeting MAM could be therapeutically beneficial in this disorder this disoefdisorder.
    Keywords:  ALS; Lipid homeostasis; MAM dysfunction
  6. J Gerontol A Biol Sci Med Sci. 2021 Mar 11. pii: glab077. [Epub ahead of print]
      Periods of inactivity experienced by older adults induce nutrient anabolic resistance creating a cascade of skeletal muscle transcriptional and translational aberrations contributing to muscle dysfunction. The purpose of this study was to identify how inactivity alters leucine-stimulated translation of molecules and pathways within the skeletal muscle of older adults. We performed ribosomal profiling alongside RNA sequencing from skeletal muscle biopsies taken from older adults (n=8; ~72y; 6F/2M) in response to a leucine bolus before (Active) and after (Reduced Activity) 2-weeks of reduced physical activity. At both visits, muscle biopsies were taken at baseline, 60min (early response), and 180min (late response) after leucine ingestion. Previously identified inactivity-related gene transcription changes (PFKFB3, GADD45A, NMRK2) were heightened by leucine with corresponding changes in translation. In contrast, leucine also stimulated translational efficiency (T.E.) of several transcripts in a manner not explained by corresponding changes in mRNA abundance ("uncoupled translation"). Inactivity eliminated this uncoupled translational response for several transcripts, and reduced the translation of most mRNAs encoding for ribosomal proteins. Ingenuity Pathway Analysis identified discordant circadian translation and transcription as a result of inactivity such as translation changes to PER2 and PER3 despite unchanged transcription. We demonstrate inactivity alters leucine-stimulated "uncoupled translation" of ribosomal proteins and circadian regulators otherwise not detectable by traditional RNA-sequencing. Innovative techniques such as ribosomal profiling continues to further our understanding of how physical activity mediates translational regulation, and will set a path towards therapies that can restore optimal protein synthesis on the transcript specific level to combat negative consequences of inactivity on aging muscle.
    Keywords:  Aging; Circadian Rhythm; Disuse; Translation; ribosome profiling
  7. Eur J Appl Physiol. 2021 Mar 07.
      PURPOSE: Aging is associated with increased myocellular stress and loss of muscle mass and function. Heat shock proteins (HSPs) are upregulated during periods of stress as part of the cells protective system. Exercise can affect both acute HSP regulation and when repeated regularly counteract unhealthy age-related changes in the muscle. Few studies have investigated effects of exercise on HSP content in elderly. The aim of the study was to compare muscular HSP levels in young and elderly and to investigate how training affects HSP content in muscles from aged males and females.METHODS: Thirty-eight elderly were randomized to 12 weeks of strength training (STG), functional strength training (FTG) or a control group (C). To compare elderly to young, 13 untrained young performed 11 weeks of strength training (Y). Muscle biopsies were collected before and after the intervention and analyzed for HSP27, αB-crystallin and HSP70.
    RESULTS: Baseline HSP70 were 35% higher in elderly than in young, whereas there were no differences between young and elderly in HSP27 or αB-crystallin. After the training intervention, HSP70 were reduced in STG (- 33 ± 32%; P = 0.001) and FTG (- 28 ± 30%; P = 0.012). The decrease in HSP70 was more pronounced in the oldest. In contrast, Y increased HSP27 (134 ± 1%; P < 0.001) and αB-crystallin (84 ± 94%; P = 0.008).
    CONCLUSION: Twelve weeks of STG or FTG decreased the initial high levels of HSP70 in aged muscles. Thus, regular strength training can normalize some of the increases in cellular stress associated with normal aging, and lead to a healthier cellular environment in aged muscle cells.
    Keywords:  Aging; Functional training; Heat shock protein; Skeletal muscle; Strength training
  8. Biochim Biophys Acta Mol Cell Res. 2021 Mar 08. pii: S0167-4889(21)00055-0. [Epub ahead of print] 119001
      Endoplasmic Reticulum (ER) stress signaling is an adaptive mechanism triggered when protein folding demand overcomes the folding capacity of this compartment, thereby leading to the accumulation of improperly folded proteins. This stress signaling pathway is named the Unfolded Protein Response (UPR) and aims at restoring ER homeostasis. However, if this fails, mechanisms orienting cells towards death processes are initiated. Herein, we summarize the most recent findings connecting ER stress and the UPR with identified death mechanisms including apoptosis, necrosis, pyroptosis, ferroptosis, and autophagy. We highlight new avenues that could be investigated and controlled through actionable mechanisms in physiology and pathology.
    Keywords:  Apoptosis; Autophagy; Cell death; Endoplasmic reticulum; Ferroptosis; Pyroptosis; Unfolded protein response