Abstract

Accumulating evidence from several groups supports the concept that the decreased force and increased susceptibility to damage in muscles of mdx mice (mouse model for Duchenne muscular dystrophy) correlates with the presence of a significant number of malformed myofibers, which themselves generate decreased force and damage more readily. The occurrence of malformed myofibers also increases dramatically in aged mdx muscles, potentially accounting for the age-dependent increase in the susceptibility to muscle damage in the mdx. We will test this hypothesis in dystrophic and injured skeletal muscle through 2 specific aims: 1) to compare the prevalence, structure, and functional properties of myofibers with altered morphology in several models of dystrophic skeletal muscle, and 2) to link the cellular changes (e.g. morphology, histopathology, etc) to the more clinical changes (e.g. force loss and medical imaging) that occur after muscle injury. Throughout both aims, we will relate the changes seen at the cellular level to changes seen using non-invasive MRI imaging. Results of this critical comparison will be important as we seek more precise and reliable non-invasive measures to follow the temporal progression of the dystrophic process in children, and novel therapies to treat acute muscle injury.

Public Health Relevance

We know a great deal about diagnosing muscle injuries and the genetic basis of muscular dystrophies, but the pathophysiology is less clear. Fibers with abnormal morphology have been identified in diseased, regenerating, and exercised muscle, yet their frequency and functional significance remain unclear. The impact of our findings will be of value in monitoring muscular dystrophy disease progression in animal models and could be useful in following the course of chronic muscle diseases in humans. There is keen interest in identifying specific pathological processes in order to develop rationale therapies, but also to use biological markers and outcome measures that can monitor the response to therapies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR059179-02
Application #
8105061
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$291,600
Indirect Cost

  Institution

Name
University of Maryland Baltimore
Department
Orthopedics
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201

  Publications

Pratt, Stephen J P; Iyer, Shama R; Shah, Sameer B et al. (2018) Imaging Analysis of the Neuromuscular Junction in Dystrophic Muscle. Methods Mol Biol 1687:57-72
Jackson, Kathryn C; Tarpey, Michael D; Valencia, Ana P et al. (2018) Induced Cre-mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high-fat diet. FASEB J 32:3070-3084
Valencia, Ana P; Iyer, Shama R; Spangenburg, Espen E et al. (2017) Impaired contractile function of the supraspinatus in the acute period following a rotator cuff tear. BMC Musculoskelet Disord 18:436
Sanchez, Benjamin; Iyer, Shama R; Li, Jia et al. (2017) Non-invasive assessment of muscle injury in healthy and dystrophic animals with electrical impedance myography. Muscle Nerve 56:E85-E94
Iyer, Shama R; Valencia, Ana P; Hernández-Ochoa, Erick O et al. (2016) In Vivo Assessment of Muscle Contractility in Animal Studies. Methods Mol Biol 1460:293-307
Lyons, James S; Iyer, Shama R; Lovering, Richard M et al. (2016) Novel multi-functional fluid flow device for studying cellular mechanotransduction. J Biomech 49:4173-4179
Hernández-Ochoa, Erick O; Vanegas, Camilo; Iyer, Shama R et al. (2016) Alternating bipolar field stimulation identifies muscle fibers with defective excitability but maintained local Ca(2+) signals and contraction. Skelet Muscle 6:6
Valencia, Ana P; Iyer, Shama R; Pratt, Stephen J P et al. (2016) A method to test contractility of the supraspinatus muscle in mouse, rat, and rabbit. J Appl Physiol (1985) 120:310-7
Pratt, Stephen J P; Valencia, Ana P; Le, Gloribel K et al. (2015) Pre- and postsynaptic changes in the neuromuscular junction in dystrophic mice. Front Physiol 6:252
Roche, Joseph A; Tulapurkar, Mohan E; Mueller, Amber L et al. (2015) Myofiber damage precedes macrophage infiltration after in vivo injury in dysferlin-deficient A/J mouse skeletal muscle. Am J Pathol 185:1686-98

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