Inhibiting myosin-ATPase reveals a dynamic range of mitochondrial respiratory control in skeletal muscle

Perry, Christopher G. R.; Kane, Daniel A.; Lin, Chien-Te; Kozy, Rachel; Cathey, Brook L.; Lark, Daniel S.; Kane, Constance L.; Brophy, Patricia; Gavin, Timothy P.; Anderson, Ethan J.; Neufer, P. Darrell

doi:10.1042/bj20110366

Cited by 156 publications

(223 citation statements)

References 31 publications

Supporting

Mentioning

214

Contrasting

Order By: Relevance

“…Furthermore, recent evidence demonstrates that mitochondrial affinity for ADP is modulated by the contractile state of myofibers (76), with contraction lowering the K m for ADP. This effect was more pronounced in fast fibers, suggesting that different mechanisms linking contractile state and mitochondrial energy exchange may exist between slow and fast muscles (76).…”

Section: Regulation Of Respiration By Adp and Mitochondrial Cou-mentioning

confidence: 87%

Mitochondrial functional specialization in glycolytic and oxidative muscle fibers: tailoring the organelle for optimal function

Picard

Hepple

Burelle

2012

American Journal of Physiology-Cell Physiology

174

128

View full text Add to dashboard Cite

Picard M, Hepple RT, Burelle Y. Mitochondrial functional specialization in glycolytic and oxidative muscle fibers: tailoring the organelle for optimal function. Am J Physiol Cell Physiol 302: C629 -C641, 2012. First published October 26, 2011; doi:10.1152/ajpcell.00368.2011In skeletal muscle, two major types of muscle fibers exist: slow-twitch oxidative (type I) fibers designed for low-intensity long-lasting contractions, and fast-twitch glycolytic (type II) fibers designed for high-intensity short-duration contractions. Such a wide range of capabilities has emerged through the selection across fiber types of a narrow set of molecular characteristics suitable to achieve a specific contractile phenotype. In this article we review evidence supporting the existence of distinct functional phenotypes in mitochondria from slow and fast fibers that may be required to ensure optimal muscle function. This includes differences with respect to energy substrate preferences, regulation of oxidative phosphorylation, dynamics of reactive oxygen species, handling of Ca 2ϩ , and regulation of cell death. The potential physiological implications on muscle function and the putative mechanisms responsible for establishing and maintaining distinct mitochondrial phenotype across fiber types are also discussed. mitochondria; reactive oxygen species; calcium retention capacity; oxidative capacity SKELETAL MUSCLE FIBERS are fantastic molecular and metabolic machines that have developed through evolution a large scope of contractile properties, ranging from slow contracting, lowpowered fibers designed for endurance, to fast contracting, high-powered fibers designed for short bursts of high-intensity work. Such a wide range of functional specialization has emerged through the selection across fiber types of optimal cytoarchitectural configurations, and expression of specific isoforms for most molecular components of myofibers including, among others, sarcomeres, excitation-contraction coupling machinery, and energy metabolism pathways. Importantly, in this process, evolution seems to have favored coadaptation whereby only a very narrow combination of molecular characteristics appear suitable to achieve a specific contractile phenotype (42).At the level of energy metabolism, one of the classical and distinctive features differentiating fiber types is mitochondrial volume density, slow twitch type I fibers typically displaying a two-to threefold higher mitochondrial density and substantially lower capacity for nonoxidative ATP synthesis compared with fast twitch type II fibers. While this difference in mitochondrial quantity was for a long time considered the main factor that varied substantially across fiber types, studies demonstrating the existence of fiber type-specific differences in mitochondrial respiratory properties, and in mechanisms coupling mitochondria to sites of ATP consumption, have progressively contributed to change this view.More recently, studies from our laboratory (79) and others (2) have shown that marked differences...

show abstract

Section: Regulation Of Respiration By Adp and Mitochondrial Cou-mentioning

confidence: 87%

Mitochondrial functional specialization in glycolytic and oxidative muscle fibers: tailoring the organelle for optimal function

Picard

Hepple

Burelle

2012

American Journal of Physiology-Cell Physiology

174

128

View full text Add to dashboard Cite

show abstract

“…Oligomycin-inhibited respiration (state 4o) was determined in the presence of the above substrates with the addition of oligomycin (6 μg/ml). Cytochrome c (10 μmol/l) was added to the chamber to check the integrity of the outer mitochondrial membrane [24].…”

Section: Methodsmentioning

confidence: 99%

In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice

et al. 2015

View full text Add to dashboard Cite

Aims/hypothesis Consuming a high-fat diet (HFD) induces insulin resistance in white adipose tissue (WAT) within 1 week. However, little is known about the initiating events. One potential mechanism that has remained largely unexplored is excessive mitochondrial emission of reactive oxygen species (ROS). Methods To determine the role of mitochondrial ROS emissions at the onset of insulin resistance, wild-type (WT) mice were placed on an HFD for 1 week. WAT insulin sensitivity and inflammation were assessed by western blot. In addition, we optimised/validated a method to determine ROS emissions in permeabilised WAT. Results An HFD for 1 week resulted in impaired insulin signalling, increased c-Jun NH 2 -terminal kinase (JNK) phosphorylation and an increase in oxidative stress. These changes were associated with an increase in fatty-acid-mediated mitochondrial ROS emissions without any change in mitochondrial respiration/content. To determine that mitochondrial ROS causes insulin resistance, we used transgenic mice that express human catalase in mitochondria (MCAT) as a model of upregulated mitochondrial antioxidant enzyme capacity. MCAT mice displayed attenuated mitochondrial ROS emission, preserved insulin signalling and no inflammatory response following an HFD. Conclusions/interpretation Findings from this study suggest that elevated mitochondrial ROS emission contributes to HFD-induced WAT insulin resistance.

show abstract

“…Treatment of muscle fibers with myosin II inhibitors has been used to further characterize muscle contraction. For example, blebbistatin treatment was used to demonstrate the dynamic and variable range of mitochondrial ADP-stimulated respiratory kinetics in skeletal muscle [67], whereas BDM treatment was used to show that fibronectin/ integrin interactions are modulated by cardiomyocyte contractile status [68] and BTS treatment was used to demonstrate the structural orientation and contractile properties of skeletal muscle in zebrafish larvae [69]. These studies represent only a few of the many examples of the insight into biological processes provided by small-molecule myosin inhibitors.…”

Section: Scientific Insight From Inhibitor Usementioning

confidence: 99%

Small-Molecule Inhibitors of Myosin Proteins

et al. 2012

View full text Add to dashboard Cite

Advances in screening and computational methods have enhanced recent efforts to discover/ design small-molecule protein inhibitors. One attractive target for inhibition is the myosin family of motor proteins. Myosins function in a wide variety of cellular processes, from intracellular trafficking to cell motility, and are implicated in several human diseases (e.g., cancer, hypertrophic cardiomyopathy, deafness and many neurological disorders). Potent and selective myosin inhibitors are, therefore, not only a tool for understanding myosin function, but are also a resource for developing treatments for diseases involving myosin dysfunction or overactivity. This review will provide a brief overview of the characteristics and scientific/therapeutic applications of the presently identified small-molecule myosin inhibitors before discussing the future of myosin inhibitor and activator design.The identification and characterization of pharmacological compounds that inhibit the functional activity of one or more specific proteins or processes has been the subject of much scientific investigation. On a basic science level, these membrane-permeable compounds provide the scientific community with a tool for the targeted and functional inhibition of a given protein in the cell; a potent means of evaluating the intracellular functions of that protein [1,2]. From a biomedical standpoint, the characterization of these small-molecule inhibitors affords an opportunity for the development of novel disease treatments centering on the repression of an offensive molecule or the reversal of its downstream effects [3][4][5].At present, several complementary methods for obtaining suitable small-molecule inhibitors of specific proteins exist. Traditional methods in inhibitor discovery involve the systematic testing of a series of chemically synthesized or naturally occurring compounds. Advances in robotics and data processing have made it possible to use high-throughput screens to test libraries of thousands or even millions of potential drugs for their ability to inhibit the function of a specific protein in a targeted biochemical or cellular assay [6][7][8]. These inhibitor discovery processes are complemented by more precise methods in small-molecule inhibitor design. Structure-based methods rely on the use of x-ray crystallographic or NMRbased structures of a protein of interest to design small molecules likely to bind and inhibit protein function [9,10]. Computer-aided inhibitor design uses computational methods to optimize potential inhibitors identified by screening or structure-based methods, to virtually © 2013 Folma Buss * Author for correspondence: Tel.: +44 1223 763348, Fax: +44 1223 762640, fb207@cam.ac.uk. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance w...

show abstract

Inhibiting myosin-ATPase reveals a dynamic range of mitochondrial respiratory control in skeletal muscle

Cited by 156 publications

References 31 publications

Mitochondrial functional specialization in glycolytic and oxidative muscle fibers: tailoring the organelle for optimal function

Mitochondrial functional specialization in glycolytic and oxidative muscle fibers: tailoring the organelle for optimal function

In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice

Small-Molecule Inhibitors of Myosin Proteins

Contact Info

Product

Resources

About