bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2021‒05‒30
seven papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. J Physiol. 2021 May 25.
      KEY POINTS: A hallmark trait of aging skeletal muscle health is a reduction in size and function, which is most pronounced in the fast muscle fibers. We studied older men (74±4y) with a history of lifelong (>50y) endurance exercise to examine potential benefits for slow and fast muscle fiber size and contractile function. Lifelong endurance exercisers had slow muscle fibers that were larger, stronger, faster, and more powerful than young exercisers (25±1y) and age-matched non-exercisers (75±2y). Limited benefits with lifelong endurance exercise were noted in the fast muscle fibers. These findings suggest that additional exercise modalities (e.g., resistance exercise) or other therapeutic interventions are needed to target fast muscle fibers with age.ABSTRACT: We investigated single muscle fiber size and contractile function among three groups of men: lifelong exercisers (LLE; n = 21, 74±4y), old healthy non-exercisers (OH; n = 10, 75±2y), and young exercisers (YE; n = 10, 25±1y). On average, LLE exercised ∼5d/wk for ∼7h/wk over the past 53±6y. LLE were subdivided based on lifelong exercise intensity into performance (LLE-P, n = 14) and fitness (LLE-F, n = 7). Muscle biopsies (vastus lateralis) were examined for myosin heavy chain (MHC) slow (MHC I) and fast (MHC IIa) fiber size and function (strength, speed, power). LLE MHC I size (7624±2765 μm2 ) was 25-40% larger (P<0.001) than YE (6106±1710 μm2 ) and OH (5476±2467 μm2 ). LLE MHC I fibers were ∼20% stronger, ∼10% faster and ∼30% more powerful than YE and OH (P<0.05). In contrast, LLE MHC IIa size (6466±2659 μm2 ) was similar to OH (6237±2525 μm2 ; P = 0.854), with both groups ∼20% smaller (P<0.001) than YE (7860±1930 μm2 ). MHC IIa contractile function was variable across groups, with a hierarchical pattern (OH>LLE>YE; P<0.05) in normalized power among OH (16.7±6.4 W•L-1 ), LLE (13.9±4.5 W•L-1 ), and YE (12.4±3.5 W•L-1 ). The LLE-P and LLE-F had similar single fiber profiles with MHC I power driven by speed (LLE-P) or force (LLE-F), suggesting exercise intensity impacted slow muscle fiber mechanics. These data suggest that lifelong endurance exercise benefited slow muscle fiber size and function. Comparable fast fiber characteristics between LLE and OH, regardless of training intensity, suggest other exercise modes (e.g., resistance training) or myotherapeutics may be necessary to preserve fast muscle fiber size and performance with age. This article is protected by copyright. All rights reserved.
    Keywords:  aging; contractile function; masters athletes; myocellular; physical activity
  2. Front Mol Biosci. 2021 ;8 681237
      Mitofusin 2 (Mfn2) is a transmembrane GTPase located on the mitochondrial outer membrane that contributes to mitochondrial network regulation. It is an essential multifunctional protein that participates in various biological processes under physical and pathological conditions, including mitochondrial fusion, reticulum-mitochondria contacts, mitochondrial quality control, and apoptosis. Mfn2 dysfunctions have been found to contribute to cardiovascular diseases, such as ischemia-reperfusion injury, heart failure, and dilated cardiomyopathy. Here, this review mainly focuses on what is known about the structure and function of Mfn2 and its crucial role in heart failure.
    Keywords:  Mfn2; endoplasmic reticulum–mitochondria contacts; heart failure; mitochondria fusion; mitophagy
  3. J Physiol. 2021 May 25.
      KEY POINTS: Healthy older adults exhibit lower cardiorespiratory fitness (VO2 peak) than young in the absence of any age-related difference in skeletal muscle mitochondrial capacity, suggesting central hemodynamics plays a larger role in age-related declines in VO2 peak. Total physical activity did not differ by age, but moderate-to-vigorous physical activity was lower in older compared to young adults. Moderate-to-vigorous physical activity is associated with VO2 peak and muscle oxidative capacity, but physical inactivity cannot entirely explain the age-related reduction in VO2 peak.ABSTRACT: Declining fitness (VO2 peak) is a hallmark of aging and believed to arise from decreased oxygen delivery and reduced muscle oxidative capacity. Physical activity is a modifiable lifestyle factor that is critical when evaluating the effects of age on parameters of fitness and energy metabolism. The objective was to evaluate the effects of age and sex on VO2 peak, muscle mitochondrial physiology, and physical activity in young and older adults. An additional objective was to assess the contribution of skeletal muscle oxidative capacity to age-related reductions in VO2 peak and determine if age-related variation in VO2 peak and muscle oxidative capacity could be explained on the basis of physical activity levels. 23 young and 52 older men and women completed measurements of VO2 peak, mitochondrial physiology in permeabilized muscle fibers, and free-living physical activity by accelerometry. Regression analyses were used to evaluate associations between age and VO2 peak, mitochondrial function, and physical activity. Significant age-related reductions were observed for VO2 peak (P<0.001), but not muscle mitochondrial capacity. Total daily step counts did not decrease with age, but older adults showed lower moderate-to-vigorous physical activity, which was associated with VO2 peak (R2 = 0.323, P<0.001) and muscle oxidative capacity (R2 = 0.086, P = 0.011). After adjusting for sex and physical activity, age was negatively associated with VO2 peak but not muscle oxidative capacity. Healthy older adults exhibit lower VO2 peak but preserved mitochondrial capacity compared to young. Physical activity, particularly moderate-to-vigorous, is a key factor in observed age-related changes in fitness and muscle oxidative capacity, but cannot entirely explain the age-related reduction in VO2 peak. This article is protected by copyright. All rights reserved.
    Keywords:  ageing; mitochondria; physical activity; skeletal muscle
  4. Cell Rep. 2021 May 25. pii: S2211-1247(21)00525-8. [Epub ahead of print]35(8): 109180
      Mitochondrial respiratory complex subunits assemble in supercomplexes. Studies of supercomplexes have typically relied upon antibody-based quantification, often limited to a single subunit per respiratory complex. To provide a deeper insight into mitochondrial and supercomplex plasticity, we combine native electrophoresis and mass spectrometry to determine the supercomplexome of skeletal muscle from sedentary and exercise-trained mice. We quantify 422 mitochondrial proteins within 10 supercomplex bands in which we show the debated presence of complexes II and V. Exercise-induced mitochondrial biogenesis results in non-stoichiometric changes in subunits and incorporation into supercomplexes. We uncover the dynamics of supercomplex-related assembly proteins and mtDNA-encoded subunits after exercise. Furthermore, exercise affects the complexing of Lactb, an obesity-associated mitochondrial protein, and ubiquinone biosynthesis proteins. Knockdown of ubiquinone biosynthesis proteins leads to alterations in mitochondrial respiration. Our approach can be applied to broad biological systems. In this instance, comprehensively analyzing respiratory supercomplexes illuminates previously undetectable complexity in mitochondrial plasticity.
    Keywords:  complexome; exercise; mitochondrial respiratory complexes; mitochondrial supercomplexes; oxidative phosphorylation; protein complexes
  5. Prog Mol Subcell Biol. 2021 ;59 239-278
      Endoplasmic reticulum (ER) stress is a prominent cellular alteration of diseases impacting the nervous system that are associated to the accumulation of misfolded and aggregated protein species during aging. The unfolded protein response (UPR) is the main pathway mediating adaptation to ER stress, but it can also trigger deleterious cascades of inflammation and cell death leading to cell dysfunction and neurodegeneration. Genetic and pharmacological studies in experimental models shed light into molecular pathways possibly contributing to ER stress and the UPR activation in human neuropathies. Most of experimental models are, however, based on the overexpression of mutant proteins causing familial forms of these diseases or the administration of neurotoxins that induce pathology in young animals. Whether the mechanisms uncovered in these models are relevant for the etiology of the vast majority of age-related sporadic forms of neurodegenerative diseases is an open question. Here, we provide a systematic analysis of the current evidence linking ER stress to human pathology and the main mechanisms elucidated in experimental models. Furthermore, we highlight the recent association of metabolic syndrome to increased risk to undergo neurodegeneration, where ER stress arises as a common denominator in the pathogenic crosstalk between peripheral organs and the nervous system.
    Keywords:  Aging; ER stress; Metabolic syndrome; Neurodegenerative diseases; Protein misfolding
  6. Sci Adv. 2021 May;pii: eabf0971. [Epub ahead of print]7(22):
      In response to disturbed mitochondrial gene expression and protein synthesis, an adaptive transcriptional response sharing a signature of the integrated stress response (ISR) is activated. We report an intricate interplay between three transcription factors regulating the mitochondrial stress response: CHOP, C/EBPβ, and ATF4. We show that CHOP acts as a rheostat that attenuates prolonged ISR, prevents unfavorable metabolic alterations, and postpones the onset of mitochondrial cardiomyopathy. Upon mitochondrial dysfunction, CHOP interaction with C/EBPβ is needed to adjust ATF4 levels, thus preventing overactivation of the ATF4-regulated transcriptional program. Failure of this interaction switches ISR from an acute to a chronic state, leading to early respiratory chain deficiency, energy crisis, and premature death. Therefore, contrary to its previously proposed role as a transcriptional activator of mitochondrial unfolded protein response, our results highlight a role of CHOP in the fine-tuning of mitochondrial ISR in mammals.
  7. FASEB J. 2021 Jun;35(6): e21620
      Mitochondria are highly dynamic, maternally inherited cytoplasmic organelles, which fulfill cellular energy demand through the oxidative phosphorylation system. Besides, they play an active role in calcium and damage-associated molecular patterns signaling, amino acid, and lipid metabolism, and apoptosis. Thus, the maintenance of mitochondrial integrity and homeostasis is extremely critical, which is achieved through continual fusion and fission. Mitochondrial fusion allows the transfer of gene products between mitochondria for optimal functioning, especially under metabolic and environmental stress. On the other hand, fission is crucial for mitochondrial division and quality control. The imbalance between these two processes is associated with various ailments such as cancer, neurodegenerative and cardiovascular diseases. This review discusses the molecular mechanisms that control mitochondrial fusion and fission and how the disruption of mitochondrial dynamics manifests into various disease conditions.
    Keywords:  diseases; dynamics; fission; fusion; mitochondria