UC San Diego UC San Diego Electronic Theses and Dissertations Title SKELETAL MUSCLE ADAPTATIONS IN HAMSTRING CONTRACTURES OF CHILDREN WITH CEREBRAL PALSY Permalink https://escholarship.org/uc/item/6x99r9pq Author Smith, Lucas R. Publication Date 2011 Supplemental Material https://escholarship.org/uc/item/6x99r9pq#supplemental Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO SKELETAL MUSCLE ADAPTATIONS IN HAMSTRING CONTRACTURES OF CHILDREN WITH CEREBRAL PALSY A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Bioengineering by Lucas R. Smith Committee in charge: Professor Richard L. Lieber, Chair Professor Shankar Subramaniam, Co-Chair Professor Henry G. Chambers Professor Koichi Masuda Professor Robert L. Sah Professor Samuel R. Ward 2011 Copyright Lucas R. Smith, 2011 All rights reserved. The dissertation of Lucas R. Smith is approved, and it is acceptable in quality and form for publication on journal of physiology: Co-Chair Chair University of California, San Diego 2011 iii TABLE OF CONTENTS SIGNATURE PAGE ................................................................................................... iii TABLE OF CONTENTS ............................................................................................ iv LIST OF TABLES ..................................................................................................... viii LIST OF FIGURES ..................................................................................................... ix ACKNOWLEDGEMENTS ........................................................................................ xi VITA…………….. ...................................................................................................... xii ABSTRACT OF THE DISSERTATION ................................................................ xiv CHAPTER 1 INTRODUCTION ................................................................................. 1 1.1 General Introduction to the Dissertation ................................................ 1 1.2 Basic Principles of Muscle Physiology .................................................. 3 1.3 Basic principles of passive mechanical properties of muscle ................ 6 1.4 Basic principles of plasticity in muscle .................................................. 8 1.5 Basic principles of plasticity in muscle ................................................ 10 1.6 Histological Properties of Muscle in Cerebral Palsy ............................ 13 iv 1.7 Architectural Properties of Muscle in Cerebral Palsy .......................... 14 1.8 Biomechanical Properties of Muscle in Cerebral Palsy ................... 15 1.9 References ............................................................................................ 18 CHAPTER 2 NOVEL TRANSCRIPTIONAL PROFILE IN WRIST MUSCLES FROM CEREBRAL PALSY PATIENTS .............................................. 26 2.1 Abstract ................................................................................................. 26 2.2 Introduction .......................................................................................... 27 2.3 Methods ................................................................................................ 30 2.4 Results .................................................................................................. 37 2.5 Discussion ............................................................................................. 45 2.6 Acknowledgements .............................................................................. 54 2.7 References ............................................................................................ 55 CHAPTER 3 SYSTEMS ANALYSIS OF GENES RELATED TO SKELETAL MUSCLE FUNCTION ............................................................................. 71 3.1 Abstract ................................................................................................. 71 3.2 Introduction .......................................................................................... 72 3.3 Neuromuscular Junction ....................................................................... 74 3.4 Excitation Contraction Coupling .......................................................... 76 v 3.5 Sarcomere Contraction ......................................................................... 77 3.6 Cytoskeleton ......................................................................................... 79 3.7 Extracellular Matrix .............................................................................. 80 3.8 Energy Metabolism .............................................................................. 82 3.9 Inflammation ........................................................................................ 84 3.10 Muscle Hypertrophy and Atrophy ...................................................... 86 3.11 Muscle Fiber Type .............................................................................. 88 3.12 Conclusions ........................................................................................ 89 3.13 Acknowledgements ............................................................................ 91 3.14 References .......................................................................................... 92 CHAPTER 4 TRANSCRIPTIONAL ALTERATIONS OF HAMSTRING MUSCLE CONTRACTURES IN CHILDREN WITH CEREBRAL PALSY ..................................................................................................... 108 4.1 Abstract ............................................................................................... 108 4.2 Introduction ........................................................................................ 109 4.3 Results ................................................................................................ 112 4.4 Discussion ........................................................................................... 122 4.5 Material and Methods ......................................................................... 136 vi 4.6 Acknowledgements ............................................................................ 142 4.7 References .......................................................................................... 143 CHAPTER 5 HAMSTRING CONTRACTURES IN CHILDREN WITH SPASTIC CEREBRAL PALSY RESULT FROM A STIFFER ECM AND INCREASED IN VIVO SARCOMERE LENGTH ................... 162 5.1 Abstract ............................................................................................... 162 5.2 Introduction ........................................................................................ 163 5.3 Methods .............................................................................................. 166 5.4 Results ................................................................................................ 173 5.5 Discussion ........................................................................................... 179 5.6 Acknowledgements ............................................................................ 188 5.7 References .......................................................................................... 189 CHAPTER 6 SUMMARY AND SIGNIFICANCE ............................................... 205 6.1 Summary of Findings ......................................................................... 205 6.2 Significance of Findings ..................................................................... 208 6.3 Future Directions ................................................................................ 210 6.4 References .......................................................................................... 215 vii LIST OF TABLES Table 2.1: Table of genes within function groups related to skeletal muscle. ............. 62 Table 2.2: Quantification of gene pathways in various disease states (CP, DMD, IMB, HSP). ....................................................................................................... 63 Table 2.3: Table of the eight subjects used in this study with 2 muscles (FCU and ECRB) per patient with sex and age recorded. ........................................ 64 Table 2.4: Table of primers used for QPCR analysis. .................................................. 65 Table 4.1: Highlighted gene ontologies significantly over-represented in genes significantly altered in cerebral palsy. ................................................... 152 Table 4.2: Significantly over-represented pathways from public databases (KEGG, WikiPathway, and Pathway Commons) along with transcription factors and microRNA. ...................................................................................... 153 Table 4.3: Gene ontologies that were over-represented among genes that had a significant correlation (p < 0.05) with either fiber or fiber bundle passive stiffness measurements. ......................................................................... 155 Table 4.4: The list of genes that are significantly regulated in the same direction with cerebral palsy between the current study in hamstring muscle and a previous study in wrist muscle. ............................................................. 157 Table 5.1: Patient Parameters. .................................................................................... 196 viii LIST OF FIGURES Figure 2.1: Condition tree created using Pearson Correlation