title: Restrictions in ATP diffusion within sarcomeres can provoke ATP-depleted zones impairing exercise capacity in chronic obstructive pulmonary disease.
abstract: Chronic obstructive pulmonary disease (COPD) is characterized by the inability of patients to sustain a high level of ventilation resulting in perceived exertional discomfort and limited exercise capacity of leg muscles at average intracellular ATP levels sufficient to support contractility.
  
  
  
  Myosin ATPase activity in biopsy samples from healthy and COPD individuals was implemented as a local nucleotide sensor to determine ATP diffusion coefficients within myofibrils. Ergometric parameters clinically measured during maximal exercise tests in both groups were used to define the rates of myosin ATPase reaction and aerobic ATP re-synthesis. The obtained parameters in combination with AK- and CK-catalyzed reactions were implemented to compute the kinetic and steady-state spatial ATP distributions within control and COPD sarcomeres.
  
  
  
  The developed reaction-diffusion model of two-dimensional sarcomeric space identified similar, yet extremely low nucleotide diffusion in normal and COPD myofibrils. The corresponding spatio-temporal ATP distributions, constructed during imposed exercise, predicted in COPD sarcomeres a depletion of ATP in the zones of overlap between actin and myosin filaments along the center axis at average cytosolic ATP levels similar to healthy muscles.
  
  
  
  ATP-depleted zones can induce rigor tension foci impairing muscle contraction and increase a risk for sarcomere damages. Thus, intra-sarcomeric diffusion restrictions at limited aerobic ATP re-synthesis can be an additional risk factor contributing to the muscle contractile deficiency experienced by COPD patients.
  
  
  
  This study demonstrates how restricted substrate mobility within a cellular organelle can provoke an energy imbalance state paradoxically occurring at abounding average metabolic resources.
authors.affiliation: Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Internal Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Department of Medical Genetics, Mayo Clinic, 200 First St. SW, Rochester, MN, USA; Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: alekseev.alexey@mayo.edu.
authors.forename: Alexey E
authors.initials: AE
authors.lastname: Alekseev
authors.affiliation: Univ. Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy), Grenoble, France; Inserm, U1055, Grenoble, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Guzun
authors.affiliation: Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Internal Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Department of Medical Genetics, Mayo Clinic, 200 First St. SW, Rochester, MN, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Reyes
authors.affiliation: Univ. Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy), Grenoble, France; Inserm, U1055, Grenoble, France; Clinique Universitaire de Pneumologie, Pôle Thorax et Vaisseaux, Centre Hospitalier et Universitaire des Alpes, CS10217, 38043 Grenoble Cedex 9, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pison
authors.affiliation: Univ. Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics (LBFA), and SFR Environmental and Systems Biology (BEeSy), Grenoble, France; Inserm, U1055, Grenoble, France.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlattner
authors.affiliation: Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IBUB Barcelona, Gran Via de les Corts Catalanes 585, 08007 Barcelona, Spain.
authors.forename: Vitaly A
authors.initials: VA
authors.lastname: Selivanov
authors.affiliation: Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IBUB Barcelona, Gran Via de les Corts Catalanes 585, 08007 Barcelona, Spain. Electronic address: martacascante@ub.edu.
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000368:Aged; D001706:Biopsy; D002451:Cell Compartmentation / Q000235:genetics; D004058:Diffusion; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000502:physiology; D009210:Myofibrils / Q000378:metabolism* / Q000473:pathology; D009218:Myosins / Q000378:metabolism*; D010101:Oxygen Consumption / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology
chemical_list: D000255:Adenosine Triphosphate; D009218:Myosins
keywords: Diffusion coefficient; Intracellular compartmentation; Myosin ATPase; Oxygen consumption; Rigor tension