Novel Insights in the Function of the Giant Sarcomeric Proteins Titin and Nebulin

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The striated muscle sarcomere contains two giant proteins: titin and nebulin. Titin is a giant elastic protein (3-4 MDa) that spans the half sarcomere from Z-disc to M-band, and is responsible for a large fraction of passive stress that develops when muscle is stretched. Alternative splicing results in large fetal isoforms and smaller adult isoforms that differ mainly in the size of their extensible I-band region. Differences in the mechanical properties of these isoforms and how these properties are altered by excision of specific spring elements have been recently established using novel knockout models. Findings show that titin mechanics can be tuned by phosphorylation, including the recently discovered PKG and PKC phosphorylation pathways. Furthermore, titin-binding proteins that interact with titin along the full length of the sarcomere play a role in protein turnover, and in sensing mechanical stresses that initiate hypertrophic signaling. Nebulin is a giant 600-900 kDa filamentous protein that is an integral component of the skeletal muscle thin filament. Recent improvements in the field, especially the development of mouse models deficient in nebulin (NEB-KO mice), indicate that nebulin functions, in addition to its role in thin filament length specification, in the regulation of muscle contraction. Muscle fibers deficient in nebulin have a higher tension cost, and develop less force due to reduced myofilament calcium sensitivity and altered crossbridge cycling kinetics. These novel functions indicate that nebulin might have evolved in vertebrate skeletal muscles to efficiently develop high levels of muscle force. The NEB-KO mouse models also highlight nebulin's role in the assembly and alignment of the Z-disks. Importantly, rapid progress in understanding nebulin's in vivo roles provides clinically important insights in how nebulin deficiency in patients with nemaline myopathy contributes to debilitating muscle weakness.