Three‐dimensional reconstruction of the human skeletal muscle mitochondrial network as a tool to assess mitochondrial content and structural organization

Dahl, Rannvá; Larsen, Steen; Dohlmann, Tine Lovsø; Qvortrup, Klaus; Helge, Jørn Wulff; Dela, Flemming; Prats, Clara

doi:10.1111/apha.12289

Cited by 91 publications

(79 citation statements)

References 33 publications

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“…Although connected to the IMF pool (14), SS mitochondria comprise only 20% of myocellular mitochondria and are located distal to most myofilaments. However, compared with the IMF pool, SS mitochondria are more responsive to the effects of muscle use/disuse (2,3,27,36,47).…”

Section: Discussionmentioning

confidence: 99%

“…However, compared with the IMF pool, SS mitochondria are more responsive to the effects of muscle use/disuse (2,3,27,36,47). Moreover, because of their close proximity to myonuclei (14,19), alterations in SS content and/or function that affect energy supply (40), reactive oxygen species production (55), and/or apoptotic stimuli (2, 3) may alter nuclear gene transcription in ways that modulate myofilament and/or mitochondrial function throughout the cell. This could occur through an effect of SS mitochondria to modulate myonuclear number, as animal models show that SS mitochondria produce more apoptotic stimuli in response to disuse (2), and it has been suggested that loss of myonuclei contributes to muscle atrophy (4).…”

Section: Discussionmentioning

confidence: 99%

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Chronic disuse and skeletal muscle structure in older adults: sex-specific differences and relationships to contractile function

Callahan

Tourville

Miller

et al. 2015

American Journal of Physiology-Cell Physiology

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Callahan DM, Tourville TW, Miller MS, Hackett SB, Sharma H, Cruickshank NC, Slauterbeck JR, Savage PD, Ades PA, Maughan DW, Beynnon BD, Toth MJ. Chronic disuse and skeletal muscle structure in older adults: sex-specific differences and relationships to contractile function. Am J Physiol Cell Physiol 308: C932-C943, 2015. First published March 25, 2015; doi:10.1152/ajpcell.00014.2015.-In older adults, we examined the effect of chronic muscle disuse on skeletal muscle structure at the tissue, cellular, organellar, and molecular levels and its relationship to muscle function. Volunteers with advanced-stage knee osteoarthritis (OA, n ϭ 16) were recruited to reflect the effects of chronic lower extremity muscle disuse and compared with recreationally active controls (n ϭ 15) without knee OA but similar in age, sex, and health status. In the OA group, quadriceps muscle and single-fiber cross-sectional area were reduced, with the largest reduction in myosin heavy chain IIA fibers. Myosin heavy chain IIAX fibers were more prevalent in the OA group, and their atrophy was sex-specific: men showed a reduction in crosssectional area, and women showed no differences. Myofibrillar ultrastructure, myonuclear content, and mitochondrial content and morphology generally did not differ between groups, with the exception of sex-specific adaptations in subsarcolemmal (SS) mitochondria, which were driven by lower values in OA women. SS mitochondrial content was also differently related to cellular and molecular functional parameters by sex: greater SS mitochondrial content was associated with improved contractility in women but reduced function in men.Collectively, these results demonstrate sex-specific structural phenotypes at the cellular and organellar levels with chronic disuse in older adults, with novel associations between energetic and contractile systems. mitochondria; physical activity; ultrastructure; myosin AGING AND DISEASE are frequently accompanied by reduced functional capacity and the development of physical disability (18). Reductions in physical activity with age are well documented (28,60,68) and promote chronic disease (31,44,53) and disability. As a result of their temporal coordination, it is difficult to disentangle the relative influence of age, disease, and physical inactivity on skeletal muscle biology and, in turn, the progression toward physical disability. Indeed, many of the muscle phenotypes that accompany aging and chronic disease, such as atrophy and contractile dysfunction, closely mimic those that accompany muscle disuse (1,46). Whether developed gradually or rapidly following a clinical event, muscle disuse in chronic conditions, such as heart failure or chronic obstructive pulmonary disease, is characterized by its persistent nature, as numerous studies reveal reduced habitual activity levels in these populations (28,60,68). Our understanding of the effects of chronic disuse on skeletal muscle size and structure is limited, in part, by the fact that it would be unethical to experimentally impose ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chronic disuse and skeletal muscle structure in older adults: sex-specific differences and relationships to contractile function

Callahan

Tourville

Miller

et al. 2015

American Journal of Physiology-Cell Physiology

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“…However, this technology is not available to all research labs and is not ideal for in vivo studies. To address the significance of mitochondrial morphology in tissue, 3-dimensional (3-D) reconstructions using either confocal microscopy or electron microscopy provide evidence that the subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial membranes physically interact in mouse and human skeletal muscle (Dahl et al, 2015; Picard et al, 2013). A recent paper extends these studies using quantitative 2-D transmission electron microscopy (TEM) to show that fusion indexes (Mfn2:Drp1 ratio) increase in aged muscle, possibly related to changes in mitochondrial morphology that contribute to mitochondrial dysfunction and sarcopenia (Leduc-Gaudet et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Analysis of mitochondrial structure and function in the Drosophila larval musculature

2016

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Mitochondria are dynamic organelles that change their architecture in normal physiological conditions. Mutations in genes that control mitochondrial fission or fusion, such as dynamin-related protein (Drp1), Mitofusins 1 (Mfn1) and 2 (Mfn2), and Optic atrophy 1 (Opa1), result in neuropathies or neurodegenerative diseases. It is increasingly clear that altered mitochondrial dynamics also underlie the pathology of other degenerative diseases, including Parkinson’s disease (PD). Thus, understanding mitochondrial distribution, shape, and dynamics in all cell types is a prerequisite for developing and defining treatment regimens that may differentially affect tissues. The majority of Drosophila genes implicated in mitochondrial dynamics have been studied in the adult indirect flight muscle (IFM). Here, we discuss the utility of Drosophila third instar larvae (L3) as an alternative model to analyze and quantify mitochondrial behaviors. Advantages include large muscle cell size, a stereotyped arrangement of mitochondria that is conserved in mammalian muscles, and the ability to analyze muscle-specific gene function in mutants that are lethal prior to adult stages. In particular, we highlight methods for sample preparation and analysis of mitochondrial morphological features.

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“…We subsequently used dSTORM for the first time in a recent study to characterise the nano-architecture of the previously detected subsarcolemmal components 56 of the mammalian skeletal muscle ttubules that had been filled with fixable fluorescent dextrans. 37 Facilitating the fast propagation of action potentials, 57 buffering ion exchange between the external space and deeper t-tubules and/or communication with the tubular extensions of subsarcolemmal mitochondria (recently visualised with deconvolved confocal micrographs and focused ion beam SEM reconstructions 58 ) are all possible functional roles of these tubules. dSTORM images of deeper tubules in rat skeletal muscle have since emerged, 59 although quantitative measurements are yet to be described.…”

Section: Fig 3 Comparison Of Micron-and Nanometre-scale Morphologies mentioning

confidence: 99%

Revealing t-tubules in striated muscle with new optical super-resolution microscopy techniques

et al. 2014

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The t-tubular system plays a central role in the synchronisation of calcium signalling and excitation-contraction coupling in most striated muscle cells. Light microscopy has been used for imaging t-tubules for well over 100 years and together with electron microscopy (EM), has revealed the three-dimensional complexities of the t-system topology within cardiomyocytes and skeletal muscle fibres from a range of species. The emerging super-resolution single molecule localisation microscopy (SMLM) techniques are offering a near 10-fold improvement over the resolution of conventional fluorescence light microscopy methods, with the ability to spectrally resolve nanometre scale distributions of multiple molecular targets. In conjunction with the next generation of electron microscopy, SMLM has allowed the visualisation and quantification of intricate t-tubule morphologies within large areas of muscle cells at an unprecedented level of detail. In this paper, we review recent advancements in the ttubule structural biology with the utility of various microscopy techniques. We outline the technical considerations in adapting SMLM to study t-tubules and its potential to further our understanding of the molecular processes that underlie the sub-micron scale structural alterations observed in a range of muscle pathologies.

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Three‐dimensional reconstruction of the human skeletal muscle mitochondrial network as a tool to assess mitochondrial content and structural organization

Cited by 91 publications

References 33 publications

Chronic disuse and skeletal muscle structure in older adults: sex-specific differences and relationships to contractile function

Chronic disuse and skeletal muscle structure in older adults: sex-specific differences and relationships to contractile function

Analysis of mitochondrial structure and function in the Drosophila larval musculature

Revealing t-tubules in striated muscle with new optical super-resolution microscopy techniques

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