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Review

N2A Titin: Signaling Hub and Mechanical Switch in Skeletal Muscle

1
Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011-5640, USA
2
Institute of Physiology II, University of Münster, 48149 Münster, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(11), 3974; https://doi.org/10.3390/ijms21113974
Received: 12 May 2020 / Revised: 30 May 2020 / Accepted: 1 June 2020 / Published: 1 June 2020
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease)
Since its belated discovery, our understanding of the giant protein titin has grown exponentially from its humble beginning as a sarcomeric scaffold to recent recognition of its critical mechanical and signaling functions in active muscle. One uniquely useful model to unravel titin’s functions, muscular dystrophy with myositis (mdm), arose spontaneously in mice as a transposon-like LINE repeat insertion that results in a small deletion in the N2A region of titin. This small deletion profoundly affects hypertrophic signaling and muscle mechanics, thereby providing insights into the function of this specific region and the consequences of its dysfunction. The impact of this mutation is profound, affecting diverse aspects of the phenotype including muscle mechanics, developmental hypertrophy, and thermoregulation. In this review, we explore accumulating evidence that points to the N2A region of titin as a dynamic “switch” that is critical for both mechanical and signaling functions in skeletal muscle. Calcium-dependent binding of N2A titin to actin filaments triggers a cascade of changes in titin that affect mechanical properties such as elastic energy storage and return, as well as hypertrophic signaling. The mdm phenotype also points to the existence of as yet unidentified signaling pathways for muscle hypertrophy and thermoregulation, likely involving titin’s PEVK region as well as the N2A signalosome. View Full-Text
Keywords: mechano-sensing; muscle hypertrophy; muscle mechanics; muscular dystrophy; striated muscle; titinopathy mechano-sensing; muscle hypertrophy; muscle mechanics; muscular dystrophy; striated muscle; titinopathy
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MDPI and ACS Style

Nishikawa, K.; Lindstedt, S.L.; Hessel, A.; Mishra, D. N2A Titin: Signaling Hub and Mechanical Switch in Skeletal Muscle. Int. J. Mol. Sci. 2020, 21, 3974. https://doi.org/10.3390/ijms21113974

AMA Style

Nishikawa K, Lindstedt SL, Hessel A, Mishra D. N2A Titin: Signaling Hub and Mechanical Switch in Skeletal Muscle. International Journal of Molecular Sciences. 2020; 21(11):3974. https://doi.org/10.3390/ijms21113974

Chicago/Turabian Style

Nishikawa, Kiisa, Stan L. Lindstedt, Anthony Hessel, and Dhruv Mishra. 2020. "N2A Titin: Signaling Hub and Mechanical Switch in Skeletal Muscle" International Journal of Molecular Sciences 21, no. 11: 3974. https://doi.org/10.3390/ijms21113974

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