bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2021‒07‒11
eight papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Cell Mol Life Sci. 2021 Jul 06.
      Mitochondrial fidelity is a key determinant of longevity and was found to be perturbed in a multitude of disease contexts ranging from neurodegeneration to heart failure. Tight homeostatic control of the mitochondrial proteome is a crucial aspect of mitochondrial function, which is severely complicated by the evolutionary origin and resulting peculiarities of the organelle. This is, on one hand, reflected by a range of basal quality control factors such as mitochondria-resident chaperones and proteases, that assist in import and folding of precursors as well as removal of aggregated proteins. On the other hand, stress causes the activation of several additional mechanisms that counteract any damage that may threaten mitochondrial function. Countermeasures depend on the location and intensity of the stress and on a range of factors that are equipped to sense and signal the nature of the encountered perturbation. Defective mitochondrial import activates mechanisms that combat the accumulation of precursors in the cytosol and the import pore. To resolve proteotoxic stress in the organelle interior, mitochondria depend on nuclear transcriptional programs, such as the mitochondrial unfolded protein response and the integrated stress response. If organelle damage is too severe, mitochondria signal for their own destruction in a process termed mitophagy, thereby preventing further harm to the mitochondrial network and allowing the cell to salvage their biological building blocks. Here, we provide an overview of how different types and intensities of stress activate distinct pathways aimed at preserving mitochondrial fidelity.
    Keywords:  DELE1; Integrated stress response (ISR); Mitochondria; Mitochondrial unfolded protein response (UPRmt); Mitophagy; Protein import
  2. Aging Cell. 2021 Jul 03. e13419
      Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) protects cardiac function against ischemia/reperfusion (I/R) injury. Mitochondria are critical in response to myocardial I/R injury as disturbance of mitochondrial dynamics contributes to cardiac dysfunction. It is hypothesized that SIRT1 and SIRT3 are critical components to maintaining mitochondria homeostasis especially mitochondrial dynamics to exert cardioprotective actions under I/R stress. The results demonstrated that deficiency of SIRT1 and SIRT3 in aged (24-26 months) mice hearts led to the exacerbated cardiac dysfunction in terms of cardiac systolic dysfunction, cardiomyocytes contractile defection, and abnormal cardiomyocyte calcium flux during I/R stress. Moreover, the deletion of SIRT1 or SIRT3 in young (4-6 months) mice hearts impair cardiomyocyte contractility and shows aging-like cardiac dysfunction upon I/R stress, indicating the crucial role of SIRT1 and SIRT3 in protecting myocardial contractility from I/R injury. The biochemical and seahorse analysis showed that the deficiency of SIRT1/SIRT3 leads to the inactivation of AMPK and alterations in mitochondrial oxidative phosphorylation (OXPHOS) that causes impaired mitochondrial respiration in response to I/R stress. Furthermore, the remodeling of the mitochondria network goes together with hypoxic stress, and mitochondria undergo the processes of fusion with the increasing elongated branches during hypoxia. The transmission electron microscope data showed that cardiac SIRT1/SIRT3 deficiency in aging alters mitochondrial morphology characterized by the impairment of mitochondria fusion under I/R stress. Thus, the age-related deficiency of SIRT1/SIRT3 in the heart affects mitochondrial dynamics and respiration function that resulting in the impaired contractile function of cardiomyocytes in response to I/R.
    Keywords:  SIRT1; SIRT3; aging; ischemia/reperfusion; mitochondria fission and fusion
  3. Bioengineered. 2021 Dec;12(1): 3485-3502
      Age-related skeletal muscle deterioration (sarcopenia) has a significant effect on the elderly's health and quality of life, but the molecular and gene regulatory mechanisms remain largely unknown. It is necessary to identify the candidate genes related to skeletal muscle aging and prospective therapeutic targets for effective treatments. The age-line-related genes (ALRGs) and age-line-related transcripts (ALRTs) were investigated using the gene expression profiles of GSE47881 and GSE118825 from the Gene Expression Omnibus (GEO) database. The protein-protein interaction (PPI) networks were performed to identify the key molecules with Cytoscape, and Gene Set Enrichment Analysis (GSEA) was used to clarify the potential molecular functions. Two hub molecules were finally obtained and verified with quantitative real-time PCR (qRT-PCR). The results showed that the expression of mitochondria genes involved in mitochondrial electron transport, complex assembly of the respiratory chain, tricarboxylic acid cycle, oxidative phosphorylation, and ATP synthesis were down-regulated in skeletal muscle with aging. We further identified a primary hub gene of CYCS (Cytochrome C) and a key transcription factor of ESRRA (Estrogen-related Receptor Alpha) to be associated closely with skeletal muscle aging. PCR analysis confirmed the expressions of CYCS and ESRRA in gastrocnemius muscles of mice of different ages were significantly different, and decreased gradually with age. In conclusion, the main cause of skeletal muscle aging may be the systematically reduced expression of mitochondrial functional genes. The CYCS and ESRRA may play significant roles in the progression of skeletal muscle aging and serve as potential biomarkers for future diagnosis and treatment.
    Keywords:  CYCS; ESRRA; Skeletal muscle aging; gene expression; mitochondria
  4. Am J Physiol Endocrinol Metab. 2021 07 06.
      The liver is particularly susceptible to the detrimental effects of a high fat diet (HFD), rapidly developing lipid accumulation and impaired cellular homeostasis. Recently, dietary nitrate has been shown to attenuate HFD-induced whole body glucose intolerance and liver steatosis, however the underlying mechanism(s) remain poorly defined. In the current study we investigated the ability of dietary nitrate to minimize possible impairments in liver mitochondrial bioenergetics following 8 wk of HFD (60% fat) in male C57BL/6J mice. Consumption of a HFD caused whole-body glucose intolerance (p<0.0001), and within the liver, increased lipid accumulation (p<0.0001), mitochondrial-specific reactive oxygen species emission (p=0.007), and markers of oxidative stress. Remarkably, dietary nitrate attenuated almost all of these pathological responses. Despite the reduction in lipid accumulation and redox stress (reduced TBARS and nitrotyrosine), nitrate did not improve insulin signaling within the liver or whole-body pyruvate tolerance (p=0.313 HFD vs HFD+nitrate). Moreover, the beneficial effects of nitrate were independent of changes in weight gain, 5' AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) signaling, mitochondrial content, mitochondrial respiratory capacity and ADP sensitivity or antioxidant protein content. Combined, these data suggest nitrate supplementation represents a potential therapeutic strategy to attenuate hepatic lipid accumulation and decrease mitochondrial ROS emission following HFD, processes linked to improvements in whole-body glucose tolerance. However, the beneficial effects of nitrate within the liver do not appear to be a result of increased oxidative capacity or mitochondrial substrate sensitivity.
    Keywords:  Mitochondria; ROS; high fat diet; liver; nitrate
  5. J Cachexia Sarcopenia Muscle. 2021 Jul 04.
      BACKGROUND: Due to the interaction between skeletal muscle ageing and lifestyle factors, it is often challenging to attribute the decline in muscle mass and quality to either changes in lifestyle or to advancing age itself. Because many of the physiological factors affecting muscle mass and quality are modulated by physical activity and physical activity declines with age, the aim of this study is to better understand the effects of early ageing on muscle function by comparing a population of healthy older and young males with similar physical activity patterns.METHODS: Eighteen older (69 ± 2.0 years) and 20 young (22 ± 2.0 years) males were recruited based on similar self-reported physical activity, which was verified using accelerometry measurements. Gene expression profiles of vastus lateralis biopsies obtained by RNA sequencing were compared, and key results were validated using quantitative polymerase chain reaction and western blot.
    RESULTS: Total physical activity energy expenditure was similar between the young and old group (404 ± 215 vs. 411 ± 189 kcal/day, P = 0.11). Three thousand seven hundred ninety-seven differentially expressed coding genes (DEGs) were identified (adjusted P-value cut-off of <0.05), of which 1891 were higher and 1906 were lower expressed in the older muscle. The matrisome, innervation and inflammation were the main upregulated processes, and oxidative metabolism was the main downregulated process in old compared with young muscle. Lower protein levels of mitochondrial transcription factor A (TFAM, P = 0.030) and mitochondrial respiratory Complexes IV and II (P = 0.011 and P = 0.0009, respectively) were observed, whereas a trend was observed for Complex I (P = 0.062), in older compared with young muscle. Protein expression of Complexes I and IV was significantly correlated to mitochondrial capacity in the vastus lateralis as measured in vivo (P = 0.017, R2  = 0.42 and P = 0.030, R2  = 0.36). A trend for higher muscle-specific receptor kinase (MUSK) protein levels in the older group was observed (P = 0.08).
    CONCLUSIONS: There are clear differences in the transcriptome signatures of the vastus lateralis muscle of healthy older and young males with similar physical activity levels, including significant differences at the protein level. By disentangling physical activity and ageing, we appoint early skeletal muscle ageing processes that occur despite similar physical activity. Improved understanding of these processes will be key to design targeted anti-ageing therapies.
    Keywords:  Matrisome; Mitochondrial capacity; Muscle ageing; Physical activity
  6. Med Res Arch. 2020 Feb;pii: 2049. [Epub ahead of print]8(2):
      The impact of type 1 diabetes (T1D) on muscle endurance and oxidative capacity is currently unknown.Purpose: Measure muscle endurance and oxidative capacity of adults with T1D compared to controls.
    Methods: A cross-sectional study design with a control group was used. Subjects (19-37 years old) with T1D (n=17) and controls (n=17) were assessed with hemoglobin A1c (HbA1c) and casual glucose. Muscle endurance was measured with an accelerometer at stimulation frequencies of 2, 4, and 6 Hz for a total of nine minutes. Mitochondrial capacity was measured using near-infrared spectroscopy after exercise as the rate constant of the rate of recovery of oxygen consumption.
    Results: T1D and control groups were similar in age, sex, height, and race. The T1D group had slightly higher BMI values and adipose tissue thickness over the forearm muscles. Casual glucose was 150±70 mg/dL for T1D and 98±16 mg/dL for controls (P=0.006). HbA1c of T1D subjects was 7.1±0.9% and 5.0±0.4% for controls (P<0.01). Endurance indexes at 2, 4, and 6 Hz were 94.5±5.2%, 81.8±8.4%, and 68.6±13.5% for T1D and 94.6±4.1%, 85.9±6.3%, and 68.7±15.4% for controls (p = 0.97, 0.12, 0.99, respectively). There were no differences between groups in mitochondrial capacity (T1D= 1.9±0.5 min-1 and control=1.8±0.4 min-1, P=0.29) or reperfusion rate (T1D= 8.8±2.8s and control=10.3±3.0s, P=0.88). There were no significant correlations between HbA1c and either muscle endurance, mitochondrial capacity or reperfusion rate.
    Conclusions: Adults with T1D did not have reduced oxidative capacity, muscle endurance or muscle reperfusion rates compared to controls. HbA1c also did not correlate with muscle endurance, mitochondrial capacity or reperfusion rates. Future studies should extend these measurements to older people or people with poorly-controlled T1D.
    Keywords:  Electrical Stimulation; Fatigability; Near Infrared Spectroscopy (NIRS); skeletal muscle
  7. Cell Metab. 2021 Jul 06. pii: S1550-4131(21)00278-3. [Epub ahead of print]33(7): 1274-1275
      Numerous preclinical studies implicate the decline in NAD+ signaling in developing aging- and obesity-associated metabolic disorders. Yoshino et al. (2021) now provide the clinical evidence that an NAD+ booster increases muscle insulin sensitivity in postmenopausal prediabetic women, validating the therapeutic promises of NAD+ boosters in humans.
  8. J Int Soc Sports Nutr. 2021 Jul 08. 18(1): 54
      BACKGROUND: Recent studies in rodents indicate that a combination of exercise training and supplementation with nicotinamide adenine dinucleotide (NAD+) precursors has synergistic effects. However, there are currently no human clinical trials analyzing this.OBJECTIVE: This study investigates the effects of a combination of exercise training and supplementation with nicotinamide mononucleotide (NMN), the immediate precursor of NAD+, on cardiovascular fitness in healthy amateur runners.
    METHODS: A six-week randomized, double-blind, placebo-controlled, four-arm clinical trial including 48 young and middle-aged recreationally trained runners of the Guangzhou Pearl River running team was conducted. The participants were randomized into four groups: the low dosage group (300 mg/day NMN), the medium dosage group (600 mg/day NMN), the high dosage group (1200 mg/day NMN), and the control group (placebo). Each group consisted of ten male participants and two female participants. Each training session was 40-60 min, and the runners trained 5-6 times each week. Cardiopulmonary exercise testing was performed at baseline and after the intervention, at 6 weeks, to assess the aerobic capacity of the runners.
    RESULTS: Analysis of covariance of the change from baseline over the 6 week treatment showed that the oxygen uptake (VO2), percentages of maximum oxygen uptake (VO2max), power at first ventilatory threshold, and power at second ventilatory threshold increased to a higher degree in the medium and high dosage groups compared with the control group. However, there was no difference in VO2max, O2-pulse, VO2 related to work rate, and peak power after the 6 week treatment from baseline in any of these groups.
    CONCLUSION: NMN increases the aerobic capacity of humans during exercise training, and the improvement is likely the result of enhanced O2 utilization of the skeletal muscle.
    Keywords:  Aerobic capacity; Exercise training; NMN supplementation; Ventilatory threshold