Abstract
Ca2+-regulated contractility is a key determinant of the quality of muscles. The sarcomeric myofilament proteins are essential players in the contraction of striated muscles. The troponin complex in the actin thin filaments plays a central role in the Ca2+-regulation of muscle contraction and relaxation. Among the three subunits of troponin, the Ca2+-binding subunit troponin C (TnC) is a member of the calmodulin super family whereas troponin I (TnI, the inhibitory subunit) and troponin T (TnT, the tropomyosin-binding and thin filament anchoring subunit) are striated muscle-specific regulatory proteins. Muscle type-specific isoforms of troponin subunits are expressed in fast and slow twitch fibers and are regulated during development and aging, and in adaptation to exercise or disuse. TnT also evolved with various alternative splice forms as an added capacity of muscle functional diversity. Mutations of troponin subunits cause myopathies. Owing to their physiological and pathological importance, troponin variants can be used as specific markers to define muscle quality. In this focused review, we will explore the use of troponin variants as markers for the fiber contents, developmental and differentiation states, contractile functions, and physiological or pathophysiological adaptations of skeletal muscle. As protein structure defines function, profile of troponin variants illustrates how changes at the myofilament level confer functional qualities at the fiber level. Moreover, understanding of the role of troponin modifications and mutants in determining muscle contractility in age-related decline of muscle function and in myopathies informs an approach to improve human health.
Highlights
The sarcomere is the functional unit of striated muscles, and the sarcomeric myofilament proteins are key players in muscle functions
Humans express three myosin heavy chain (MHC) isoforms in adult skeletal muscle, MHC I, MHC IIa, and MHC IIx/d encoded by MYH7, MYH2, and MYH1 genes, respectively, as well as embryonic and neonatal isoforms encoded by MYH3 and MYH8 genes (Galler et al, 1997; Schiaffino and Reggiani, 2011)
Different from the slow and cardiac isoforms, the C-terminal region of fast troponin T (TnT) that interacts with troponin I (TnI) and troponin C (TnC) (Wei and Jin, 2016) contains a variable segment encoded by a pair of mutually exclusive exons, 16 and 17 in vertebrates
Summary
The sarcomere is the functional unit of striated muscles, and the sarcomeric myofilament proteins are key players in muscle functions. We will address the regulation and function of troponin isoforms and alternative splice forms in defining skeletal muscle fiber type, developmental and differentiation states, contractile function, age-related decline, and other physiological and pathophysiological adaptations. Fast skeletal muscle TnT is specific to fast twitch fibers, where it undergoes complex N-terminal alternative splicing to produce a high to low molecular weight switch during post-natal development (Wei and Jin, 2016).
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