bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2021‒01‒03
eleven papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Int J Mol Sci. 2020 Dec 23. pii: E91. [Epub ahead of print]22(1):
      Sarcopenia is a chronic disease characterized by the progressive loss of skeletal muscle mass, force, and function during aging. It is an emerging public problem associated with poor quality of life, disability, frailty, and high mortality. A decline in mitochondria quality control pathways constitutes a major mechanism driving aging sarcopenia, causing abnormal organelle accumulation over a lifetime. The resulting mitochondrial dysfunction in sarcopenic muscles feedbacks systemically by releasing the myomitokines fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), influencing the whole-body homeostasis and dictating healthy or unhealthy aging. This review describes the principal pathways controlling mitochondrial quality, many of which are potential therapeutic targets against muscle aging, and the connection between mitochondrial dysfunction and the myomitokines FGF21 and GDF15 in the pathogenesis of aging sarcopenia.
    Keywords:  FGF21; GDF15; fission; fusion; mitochondrial dynamics; mitokines; mitophagy; myokines; sarcopenia
  2. J Physiol. 2020 Dec 28.
      Mitochondria are dynamic organelles, intricately designed to meet cellular energy requirements. To accommodate alterations in energy demand, mitochondria have a high degree of plasticity, changing in response to transient activation of numerous stress-related pathways. This adaptive response is particularly relevant in highly metabolic tissues such as skeletal muscle, where mitochondria support numerous biological processes related to metabolism, growth and regeneration. Aerobic exercise is a potent stimulus for skeletal muscle remodeling, leading to alterations in substrate utilisation, fibre-type composition and performance. Underlying these physiological responses is a change in mitochondrial quality control (MQC), a term encompassing the co-ordination of mitochondrial synthesis (biogenesis), remodeling (dynamics) and degradation (mitophagy) pathways. Understanding of MQC in skeletal muscle and the regulatory role of aerobic exercise of this process are rapidly advancing, as are the molecular techniques allowing the study of MQC in vivo. Given the emerging link between MQC and the onset of numerous non-communicable diseases, understanding the molecular regulation of MQC and the role of aerobic exercise in this process, will have substantial future impact on therapeutic approaches to manipulate MQC and maintain mitochondrial function across healthspan. This article is protected by copyright. All rights reserved.
  3. Cell Rep. 2020 Dec 29. pii: S2211-1247(20)31543-6. [Epub ahead of print]33(13): 108554
      The mechanisms by which exercise benefits human health remain incompletely understood. With the emergence of omics techniques, mapping of the molecular response to exercise is increasingly accessible. Here, we perform an untargeted metabolomics profiling of plasma from a randomized, within-subjects, crossover study of either endurance exercise or resistance exercise, two types of skeletal muscle activity that have differential effects on human physiology. A high-resolution time-series analyses reveal shared as well as exercise-mode-specific perturbations in a multitude of metabolic pathways. Moreover, the analyses reveal exercise-induced changes in metabolites that are recognized to act as signaling molecules. Thus, we provide a metabolomic signature of how dissimilar modes of exercise affect the organism in a time-resolved fashion.
    Keywords:  endurance exercise; exercise; exerkine; metabolome; metabolomics; resistance exercise; skeletal muscle
  4. Nat Rev Mol Cell Biol. 2020 Dec 22.
      Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.
  5. Cell Rep. 2020 Dec 29. pii: S2211-1247(20)31552-7. [Epub ahead of print]33(13): 108563
      Misfolded proteins in the endoplasmic reticulum (ER) activate IRE1α endoribonuclease in mammalian cells, which mediates XBP1 mRNA splicing to produce an active transcription factor. This promotes the expression of specific genes to alleviate ER stress, thereby attenuating IRE1α. Although sustained activation of IRE1α is linked to human diseases, it is not clear how IRE1α is attenuated during ER stress. Here, we identify that Sec63 is a subunit of the previously identified IRE1α/Sec61 translocon complex. We find that Sec63 recruits and activates BiP ATPase through its luminal J-domain to bind onto IRE1α. This leads to inhibition of higher-order oligomerization and attenuation of IRE1α RNase activity during prolonged ER stress. In Sec63-deficient cells, IRE1α remains activated for a long period of time despite the presence of excess BiP in the ER. Thus, our data suggest that the Sec61 translocon bridges IRE1α with Sec63/BiP to regulate the dynamics of IRE1α signaling in cells.
    Keywords:  ER stress; IRE1; Sec61 translocon; endoplasmic reticulum; protein translocation; unfolded protein response
  6. Eur J Cell Biol. 2020 Dec 07. pii: S0171-9335(20)30083-2. [Epub ahead of print]100(1): 151144
      In response to mitochondrial damage, mitochondria activate mitochondrial dynamics to maintain normal functions, and an imbalance in mitochondrial dynamics triggers multiple programmed cell death processes. Recent studies have shown that phosphoglycerate mutase 5 (PGAM5) is associated with mitochondrial damage. PGAM5 activates mitochondrial biogenesis and mitophagy to promote a cellular compensatory response when mitochondria are mildly damaged, whereas severe damage to mitochondria leads to PGAM5 inducing excessive mitochondria fission, disruption to mitochondrial movement, and amplification of apoptosis, necroptosis and mitophagic death signals, which eventually evoke cell death. PGAM5 functions mainly through protein-protein interactions and specific Ser/Thr/His protein phosphatase activity. PGAM5 is also regulated by mitochondrial proteases. Detection of PGAM5 and its interacting protein partners should enable a more accurate evaluation of mitochondrial damage and a more precise method for the diagnosis and treatment of diseases.
    Keywords:  Apoptosis; Mitochondrial dynamics; Mitochondrial proteases; Necroptosis; PGAM5
  7. Science. 2021 Jan 01. pii: eabb6896. [Epub ahead of print]371(6524):
      Tissue homeostasis is perturbed in a diversity of inflammatory pathologies. These changes can elicit endoplasmic reticulum (ER) stress, protein misfolding, and cell death. ER stress triggers the unfolded protein response (UPR), which can promote recovery of ER proteostasis and cell survival or trigger programmed cell death. Here, we leveraged single-cell RNA sequencing to define dynamic transcriptional states associated with the adaptive versus terminal UPR in the mouse intestinal epithelium. We integrated these transcriptional programs with genome-scale CRISPR screening to dissect the UPR pathway functionally. We identified QRICH1 as a key effector of the PERK-eIF2α axis of the UPR. QRICH1 controlled a transcriptional program associated with translation and secretory networks that were specifically up-regulated in inflammatory pathologies. Thus, QRICH1 dictates cell fate in response to pathological ER stress.
  8. Int J Mol Sci. 2020 Dec 22. pii: E37. [Epub ahead of print]22(1):
      Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction.
    Keywords:  sarcopenia; sarcoplasmic reticulum calcium-transporting ATPase; skeletal muscle
  9. Exp Gerontol. 2020 Dec 26. pii: S0531-5565(20)30568-4. [Epub ahead of print]145 111220
      Aging-related changes to biological structures such as cardiovascular and musculoskeletal systems contribute to the development of comorbid conditions including cardiovascular disease and frailty, and ultimately lead to premature death. Although, frail older adults often demonstrate both cardiovascular and musculoskeletal comorbidities, the etiology of sarcopenia, and especially the contribution of cardiovascular aging is unclear. Aging-related vascular calcification is prevalent in older adults and is a known risk factor for cardiovascular disease and death. The effect vascular calcification has on function during aging is not well understood. Emerging findings suggest vascular calcification can impact skeletal muscle perfusion, negatively affecting nutrient and oxygen delivery to skeletal muscle, ultimately accelerating muscle loss and functional decline. The present review summarizes existing evidence on the biological mechanisms linking vascular calcification with sarcopenia during aging.
    Keywords:  Aging; Biology of aging; Inflammation; Oxidative stress; Skeletal muscle
  10. Front Cell Dev Biol. 2020 ;8 618322
      Lipid droplets (LDs) and mitochondria are essential organelles involved in cellular lipid metabolism and energy homeostasis. Accumulated studies have revealed that the physical contact between these two organelles is important for their functions. Current understanding of the contact between cellular organelles is highly dynamic, fitting a "kiss-and-run" model. The same pattern of contact between LDs and mitochondria has been reported and several proteins are found to mediate this contact, such as perilipin1 (PLIN1) and PLIN5. Another format of the contact has also been found and termed anchoring. LD-anchored mitochondria (LDAM) are identified in oxidative tissues including brown adipose tissue (BAT), skeletal muscle, and heart muscle, and this anchoring between these two organelles is conserved from mouse to monkey. Moreover, this anchoring is generated during the brown/beige adipocyte differentiation. In this review, we will summarize previous studies on the interaction between LDs and mitochondria, categorize the types of the contacts into dynamic and stable/anchored, present their similarities and differences, discuss their potential distinct molecular mechanism, and finally propose a working hypothesis that may explain why and how cells use two patterns of contact between LDs and mitochondria.
    Keywords:  anchor; centrifugal force; contact; isolation; lipid droplets; mitochondria
  11. Muscle Nerve. 2021 Jan 01.
      INTRODUCTION: Skeletal muscle inflammation and oxidative stress are associated with aging-related loss of muscle mass and may be attributable to alterations in the number and types of leukocytes in skeletal muscle. Here, we tested the hypothesis that aging changes the number and composition of leukocyte subsets in skeletal muscle tissue.METHODS: Skeletal muscle was sampled from 4-month-old (young) and 27-month-old (old) C57BL/6J mice. Mononuclear cells of the gastrocnemius muscle were isolated, and flow cytometry was used to characterize the number and types of immune cells.
    RESULTS: The number of neutrophils and Ly-6C+ inflammatory macrophages in the skeletal muscle was significantly higher in old mice than in young mice. Inflammation and oxidative stress (measured using the markers phosphorylated JNK and nitrotyrosine) were also higher in the skeletal muscle of old mice than in that of young mice.
    DISCUSSION: Increasing age promotes skeletal muscle inflammation and oxidative stress, as well as infiltration of inflammatory macrophages and neutrophils.
    Keywords:  Increasing age; Inflammation; Loss of muscle mass; Macrophage; Oxidative stress