The Role of Sarcomeric Proteins and Their Post-translational Modifications in Striated Muscle Health, Disease, and Aging

Released on by Zachery Robert Gregorich
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  • The Role of Sarcomeric Proteins and Their Post-translational Modifications in Striated Muscle Health, Disease, and Aging Book Detail

  • Author : Zachery Robert Gregorich
  • Release Date : 2017
  • Publisher :
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  • Pages : 0
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  • File Size : 53,53 MB
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The Role of Sarcomeric Proteins and Their Post-translational Modifications in Striated Muscle Health, Disease, and Aging by Zachery Robert Gregorich PDF Summary

Book Description: Sarcomeric proteins, including both myofilament and Z-disc proteins, constitute the molecular machinery responsible for force production in a Ca2+-dependent manner. In addition to regulation by Ca2+, convincing evidence now indicates that the post-translational modification (PTM) of myofilament proteins is an essential mechanism enabling the Ca2+-independent modulation of striated muscle contractility. Moreover, the view of the Z-discs as passive structures, necessary only for force transmission between adjacent sarcomeres, has undergone a paradigm shift, with the results of recent studies implicating these structures in signaling, and even in the regulation of striated muscle contractile function. In the studies detailed in this thesis, top-down mass spectrometry-based proteomics was employed in combination with functional assays to gain insights into the role of sarcomeric proteins and their PTMs in the heart under basal conditions and in response to myocardial injury, as well as in skeletal muscle during natural aging. Collectively, the key findings presented herein shed new light on the roles of myofilament protein PTMs in cardiac and skeletal muscle contractile function under basal and pathological conditions. Also noteworthy was the identification of alterations in the phosphorylation of Z-disc proteins in cardiac and skeletal muscles in response to infarction and natural aging, respectively. These findings provide the first evidence that the Z-discs may be involved in the early events in the heart after injury and in aging skeletal muscles. Moreover, evidence that enigma homolog protein isoforms, which localize to the Z-discs in striated muscles, play a role in setting the kinetics of force redevelopment, at least in mouse myocardium, is also presented. Thus, these findings not only provide new information regarding the contributions made by myofilament protein PTMs to striated muscle contractility, but also open new avenues to explore the role of Z-disc proteins in striated muscle biology. Furthermore, these results add to a growing list of contributions made by top-down mass spectrometry to the advancement of our understanding of the functions of protein PTMs in health and disease.

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The Sarcomere and Skeletal Muscle Disease

The Sarcomere and Skeletal Muscle Disease

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Although best known for its role in heart disease, the sarcomere--the fundamental unit of muscle contraction--is also involved in skeletal muscle diseases. Chap