Dataset Information

Shorten2007_SkeletalMuscleFatigue

ABSTRACT: This a model from the article: A mathematical model of fatigue in skeletal muscle force contraction. Shorten PR, O'Callaghan P, Davidson JB, Soboleva TK. J Muscle Res Cell Motil 2007;28(6):293-313 18080210 , Abstract: The ability for muscle to repeatedly generate force is limited by fatigue. The cellular mechanisms behind muscle fatigue are complex and potentially include breakdown at many points along the excitation-contraction pathway. In this paper we construct a mathematical model of the skeletal muscle excitation-contraction pathway based on the cellular biochemical events that link excitation to contraction. The model includes descriptions of membrane voltage, calcium cycling and crossbridge dynamics and was parameterised and validated using the response characteristics of mouse skeletal muscle to a range of electrical stimuli. This model was used to uncover the complexities of skeletal muscle fatigue. We also parameterised our model to describe force kinetics in fast and slow twitch fibre types, which have a number of biochemical and biophysical differences. How these differences interact to generate different force/fatigue responses in fast- and slow- twitch fibres is not well understood and we used our modelling approach to bring new insights to this relationship. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Shorten PR, O'Callaghan P, Davidson JB, Soboleva TK. (2007) - version02 This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

SUBMITTER: Vijayalakshmi Chelliah

PROVIDER: MODEL0912160004 | BioModels | 2005-01-01

REPOSITORIES: BioModels

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Publications

A mathematical model of fatigue in skeletal muscle force contraction.

Shorten Paul R PR O'Callaghan Paul P Davidson John B JB Soboleva Tanya K TK

Journal of muscle research and cell motility 20071214 6

The ability for muscle to repeatedly generate force is limited by fatigue. The cellular mechanisms behind muscle fatigue are complex and potentially include breakdown at many points along the excitation-contraction pathway. In this paper we construct a mathematical model of the skeletal muscle excitation-contraction pathway based on the cellular biochemical events that link excitation to contraction. The model includes descriptions of membrane voltage, calcium cycling and crossbridge dynamics an ...[more]

PMID: 18080210

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Project description:Background: Niemann-Pick disease type A (NPDA), a disease caused by mutations in acid sphingomyelinase (ASM), involves severe neurodegeneration and early death. Intracellular lipid accumulation and plasma membrane alterations are implicated in the pathology. ASM is also linked to the mechanism of plasma membrane repair, so we investigated the impact of ASM deficiency in skeletal muscle, a tissue that undergoes frequent cycles of injury and repair in vivo. Methods: Utilizing the NPDA/B mouse model ASM−/− and wild type (WT) littermates, we performed excitation- contraction coupling/Ca2+ mobilization and sarcolemma injury/repair assays with isolated flexor digitorum brevis fibers, proteomic analyses with quadriceps femoris, flexor digitorum brevis, and tibialis posterior muscle and in vivo tests of the contractile force (maximal isometric torque) of the quadriceps femoris muscle before and after eccentric contraction-induced muscle injury. Results: ASM−/− flexor digitorum brevis fibers showed impaired excitation-contraction coupling compared to WT, a defect expressed as reduced tetanic [Ca2+]i in response to electrical stimulation and early failure in sustaining [Ca2+]i during repeated tetanic contractions. When injured mechanically by needle passage, ASM−/− flexor digitorum brevis fibers showed susceptibility to injury similar to WT, but a reduced ability to reseal the sarcolemma. Proteomic analyses revealed changes in a small group of skeletal muscle proteins as a consequence of ASM deficiency, with downregulation of calsequestrin occurring in the three different muscles analyzed. In vivo, the loss in maximal isometric torque of WT quadriceps femoris was similar immediately after and 2 min after injury. The loss in ASM−/− mice immediately after injury was similar to WT, but was markedly larger at 2 min after injury. Conclusions: Skeletal muscle fibers from ASM−/− mice have an impairment in intracellular Ca2+ handling that results in reduced Ca2+ mobilization and a more rapid decline in peak Ca2+ transients during repeated contraction-relaxation cycles. Isolated fibers show reduced ability to repair damage to the sarcolemma, and this is associated with an exaggerated deficit in force during recovery from an in vivo eccentric contraction- induced muscle injury. Our findings uncover the possibility that skeletal muscle functional defects may play a role in the pathology of NPDA/B disease.