bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2021‒05‒09
eleven papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Cell Rep. 2021 May 04. pii: S2211-1247(21)00420-4. [Epub ahead of print]35(5): 109087
      Parvalbumin (PV) is a cytosolic Ca2+-binding protein highly expressed in fast skeletal muscle, contributing to an increased relaxation rate. Moreover, PV is an "atrogene" downregulated in most muscle atrophy conditions. Here, we exploit mice lacking PV to explore the link between the two PV functions. Surprisingly, PV ablation partially counteracts muscle loss after denervation. Furthermore, acute PV downregulation is accompanied by hypertrophy and upregulation by atrophy. PV ablation has a minor impact on sarcoplasmic reticulum but is associated with increased mitochondrial Ca2+ uptake, mitochondrial size and number, and contacts with Ca2+ release sites. Mitochondrial calcium uniporter (MCU) silencing abolishes the hypertrophic effect of PV ablation, suggesting that mitochondrial Ca2+ uptake is required for hypertrophy. In turn, an increase of mitochondrial Ca2+ is required to enhance expression of the pro-hypertrophy gene PGC-1α4, whose silencing blocks hypertrophy due to PV ablation. These results reveal how PV links cytosolic Ca2+ control to mitochondrial adaptations, leading to muscle mass regulation.
    Keywords:  calcium buffer; mitochondria; skeletal muscle
  2. J Cachexia Sarcopenia Muscle. 2021 May 05.
      BACKGROUND: Skeletal muscle atrophy manifests across numerous diseases; however, the extent of similarities/differences in causal mechanisms between atrophying conditions in unclear. Ageing and disuse represent two of the most prevalent and costly atrophic conditions, with resistance exercise training (RET) being the most effective lifestyle countermeasure. We employed gene-level and network-level meta-analyses to contrast transcriptomic signatures of disuse and RET, plus young and older RET to establish a consensus on the molecular features of, and therapeutic targets against, muscle atrophy in conditions of high socio-economic relevance.METHODS: Integrated gene-level and network-level meta-analysis was performed on publicly available microarray data sets generated from young (18-35 years) m. vastus lateralis muscle subjected to disuse (unilateral limb immobilization or bed rest) lasting ≥7 days or RET lasting ≥3 weeks, and resistance-trained older (≥60 years) muscle.
    RESULTS: Disuse and RET displayed predominantly separate transcriptional responses, and transcripts altered across conditions were mostly unidirectional. However, disuse and RET induced directly inverted expression profiles for mitochondrial function and translation regulation genes, with COX4I1, ENDOG, GOT2, MRPL12, and NDUFV2, the central hub components of altered mitochondrial networks, and ZMYND11, a hub gene of altered translation regulation. A substantial number of genes (n = 140) up-regulated post-RET in younger muscle were not similarly up-regulated in older muscle, with young muscle displaying a more pronounced extracellular matrix (ECM) and immune/inflammatory gene expression response. Both young and older muscle exhibited similar RET-induced ubiquitination/RNA processing gene signatures with associated PWP1, PSMB1, and RAF1 hub genes.
    CONCLUSIONS: Despite limited opposing gene profiles, transcriptional signatures of disuse are not simply the converse of RET. Thus, the mechanisms of unloading cannot be derived from studying muscle loading alone and provides a molecular basis for understanding why RET fails to target all transcriptional features of disuse. Loss of RET-induced ECM mechanotransduction and inflammatory profiles might also contribute to suboptimal ageing muscle adaptations to RET. Disuse and age-dependent molecular candidates further establish a framework for understanding and treating disuse/ageing atrophy.
    Keywords:  Ageing; Gene-level analysis; Network analysis; Resistance exercise training; Skeletal muscle disuse; Transcriptomic meta-analysis
  3. Cell Metab. 2021 May 04. pii: S1550-4131(21)00174-1. [Epub ahead of print]33(5): 847-848
      Health benefits of aerobic exercise are indisputable and are closely related to the maintenance of mitochondrial energy homeostasis and insulin sensitivity. Flockhart et al. (2021) demonstrate, however, that a high volume of high-intensity aerobic exercise adversely affects mitochondrial function and may cause impaired glucose tolerance.
  4. Trends Endocrinol Metab. 2021 May 03. pii: S1043-2760(21)00075-8. [Epub ahead of print]
      PERK protein, that is canonically associated with the response to endoplasmic reticulum stress, may be acquiring a new role as a regulator of the growth of mitochondrial cristae. This role is pertinent not only to the recruitment of brown adipose tissue thermogenic capacity but probably also to directing cristae formation in highly metabolically active organs such as the heart.
    Keywords:  MICOS; brown adipose tissue; cristae; endoplasmic reticulum stress; mitochondria; norepinephrine
  5. J Physiol. 2021 May 01.
      Metabolic diseases (MetD) embrace a series of pathologies characterize by abnormal body glucose usage. The known diseases included in this group are metabolic syndrome, prediabetes and diabetes mellitus type 1 and 2, all of them are chronic pathologies that present metabolic disturbances and are classified as multi-organ diseases. Cardiomyopathy has been extensively described in diabetic patients without overt macrovascular complications. The heart is severely damaged during the progression of the disease, in fact, diabetic cardiomyopathies are the main cause of death in MetD. Insulin resistance, hyperglycemia, and increased free fatty acid metabolism promote cardiac damage through mitochondria. These organelles supply most of the energy that the heart needs to beat and control essential cellular functions, including Ca2+ signaling modulation, reactive oxygen species production, and apoptotic cell death regulation. Several aspects of the common mitochondrial functions have been described to be altered in diabetic cardiomyopathies include impairments of energy metabolism, compromises of mitochondrial dynamics, deficiencies in the Ca2+ handling, increases in ROS production, and a higher probability of mitochondrial permeability transition pore opening. Therefore, the mitochondrial role in MetD mediated heart dysfunction has been studied extensively to identify potential therapeutic targets for improving cardiac performance. Herein we review the cardiac pathology in metabolic syndrome, prediabetes, and diabetes mellitus, focusing on the role of mitochondrial dysfunctions. This article is protected by copyright. All rights reserved.
  6. J Physiol. 2021 May 07.
      Metabolic health is a crucial area of current research, and is an outcome of innate physiology, and interactions with the environment. Environmental cues, such as the Earth's day-night rhythm, partly regulate diurnal hormones and metabolites. Circadian physiology consists of highly conserved biological processes over ∼24-hour cycles, which are influenced by external cues (Zeitgebers - "time-keepers"). Skeletal muscle has diurnal variations of a large magnitude, owing in part to the strong nature of physical activity throughout the day and other external Zeitgebers. The orchestration of whole-body, and skeletal muscle metabolism is a complex, finely-tuned process, and molecular diurnal variations are regulated by a transcription-translation feedback loop controlled by the molecular clock, as well as non-transcriptional metabolic processes. The mitochondrion may play an important role in regulating diurnal metabolites within skeletal muscle, given its central role in the regulation of NAD+ /NADH, O2, reactive oxygen species and redox metabolism. These molecular pathways display diurnal variation and illustrate the complex orchestration of circadian metabolism in skeletal muscle. Probably the most robust Zeitgeber of skeletal muscle is exercise, which alters glucose metabolism and flux, in addition to a range of other diurnal metabolic pathways. Indeed, performing exercise at different times of the day may alter metabolism and health outcomes in some cohorts. The objective of this Symposium Review is to briefly cover the current literature, and to speculate regarding future areas of research. Thus, we postulate that metabolic health may be optimized by altering the timing of external cues such as diet and exercise. This article is protected by copyright. All rights reserved.
  7. Am J Physiol Cell Physiol. 2021 May 05.
      Skeletal muscle is the most abundant tissue in healthy individuals and it has important roles in health beyond voluntary movement. The overall mass and energy requirements of skeletal muscle require it to be metabolically active and flexible to multiple energy substrates. The tissue has evolved to be largely load-dependent and it readily adapts in a number of positive ways to repetitive overload, such as various forms of exercise training. However, unloading from extended bed rest and/or metabolic derangements in response to trauma, acute illness, or severe pathology, commonly result in rapid muscle wasting. Declines in muscle mass contribute to multi-morbidity, reduce function and exert a substantial, negative impact on quality of life. The principal mechanisms controlling muscle mass have been well-described and these cellular processes are intricately regulated by exercise. Accordingly, exercise has shown great promise and efficacy in preventing or slowing muscle wasting through changes in molecular physiology, organelle function, cell signaling pathways and epigenetic regulation. In this review we focus on the role of exercise in altering the molecular landscape of skeletal muscle in a manner that improves or maintains its health and function in the presence of unloading or disease.
    Keywords:  epigenetics; exercise; muscle wasting; resistance training; skeletal muscle
  8. Nature. 2021 May 05.
      Mitochondrial fission is a highly regulated process that, when disrupted, can alter metabolism, proliferation and apoptosis1-3. Dysregulation has been linked to neurodegeneration3,4, cardiovascular disease3 and cancer5. Key components of the fission machinery include the endoplasmic reticulum6 and actin7, which initiate constriction before dynamin-related protein 1 (DRP1)8 binds to the outer mitochondrial membrane via adaptor proteins9-11, to drive scission12. In the mitochondrial life cycle, fission enables both biogenesis of new mitochondria and clearance of dysfunctional mitochondria through mitophagy1,13. Current models of fission regulation cannot explain how those dual fates are decided. However, uncovering fate determinants is challenging, as fission is unpredictable, and mitochondrial morphology is heterogeneous, with ultrastructural features that are below the diffraction limit. Here, we used live-cell structured illumination microscopy to capture mitochondrial dynamics. By analysing hundreds of fissions in African green monkey Cos-7 cells and mouse cardiomyocytes, we discovered two functionally and mechanistically distinct types of fission. Division at the periphery enables damaged material to be shed into smaller mitochondria destined for mitophagy, whereas division at the midzone leads to the proliferation of mitochondria. Both types are mediated by DRP1, but endoplasmic reticulum- and actin-mediated pre-constriction and the adaptor MFF govern only midzone fission. Peripheral fission is preceded by lysosomal contact and is regulated by the mitochondrial outer membrane protein FIS1. These distinct molecular mechanisms explain how cells independently regulate fission, leading to distinct mitochondrial fates.
  9. J Cachexia Sarcopenia Muscle. 2021 May 05.
      BACKGROUND: In vivo muscle protein synthesis rates are typically assessed by measuring the incorporation rate of stable isotope labelled amino acids in skeletal muscle tissue collected from vastus lateralis muscle. It remains to be established whether muscle protein synthesis rates in the vastus lateralis are representative of muscle protein synthesis rates of other muscle groups. We hypothesized that post-absorptive muscle protein synthesis rates differ between vastus lateralis and rectus abdominis, pectoralis major, or temporalis muscle in vivo in humans.METHODS: Twenty-four patients (62 ± 3 years, 42% female), scheduled to undergo surgery, participated in this study and underwent primed continuous intravenous infusions with l-[ring-13 C6 ]-phenylalanine. During the surgical procedures, serum samples were collected, and muscle tissue was obtained from the vastus lateralis as well as from the rectus abdominis, pectoralis major, or temporalis muscle. Fractional mixed muscle protein synthesis rates (%/h) were assessed by measuring the incorporation of l-[ring-13 C6 ]-phenylalanine into muscle tissue protein.
    RESULTS: Serum l-[ring-13 C6 ]-phenylalanine enrichments did not change throughout the infusion period. Post-absorptive muscle protein synthesis rates calculated based upon serum l-[ring-13 C6 ]-phenylalanine enrichments did not differ between vastus lateralis and rectus abdominis (0.032 ± 0.004 vs. 0.038 ± 0.003%/h), vastus lateralis and pectoralis major, (0.025 ± 0.003 vs. 0.022 ± 0.005%/h) or vastus lateralis and temporalis (0.047 ± 0.005 vs. 0.043 ± 0.005%/h) muscle, respectively (P > 0.05). When fractional muscle protein synthesis rates were calculated based upon tissue-free l-[ring-13 C6 ]-phenylalanine enrichments as the preferred precursor pool, muscle protein synthesis rates were significantly higher in rectus abdominis (0.089 ± 0.008%/h) compared with vastus lateralis (0.054 ± 0.005%/h) muscle (P < 0.01). No differences were observed between fractional muscle protein synthesis rates in vastus lateralis and pectoralis major (0.046 ± 0.003 vs. 0.041 ± 0.008%/h) or vastus lateralis and temporalis (0.073 ± 0.008 vs. 0.083 ± 0.011%/h) muscle, respectively.
    CONCLUSIONS: Post-absorptive muscle protein synthesis rates are higher in rectus abdominis when compared with vastus lateralis muscle. Post-absorptive muscle protein synthesis rates do not differ between vastus lateralis and pectoralis major or temporalis muscle. Protein synthesis rates in muscle tissue samples obtained during surgery do not necessarily represent a good proxy for appendicular skeletal muscle protein synthesis rates.
    Keywords:  Cancer surgery; Pectoralis major; Protein turnover; Rectus abdominis; Stable isotope methodology; Temporalis
  10. Elife. 2021 May 04. pii: e66519. [Epub ahead of print]10
      Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response, by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, that is activated independently of BAT thermogenic function.
    Keywords:  biochemistry; chemical biology; mouse