Features of Titin and Nebulin Proteostasis in Muscles during Hibernation

The review presents data on the features of protein homeostasis (proteostasis) of the giant sarcomeric cytoskeletal proteins titin and nebulin in hibernating animals during the development of atrophic changes in skeletal muscles and the hypertrophic response in the cardiac muscle during hibernation. Maintenance of stable titin and nebulin levels results from two molecular strategies: (1) inhibition of proteolysis of the giant proteins during torpor; (2) preferential synthesis of titin and nebulin during periods of winter euthermia, accompanied by the renewal of these proteins and restoration of the quantitative content of titin reduced during hypothermia. Data are presented on the decreased quantitative content of titin and nebulin in the muscles of non-hibernating animals, as well as humans, during the development of a number of pathological processes, including hypertrophic cardiomyopathy and skeletal muscle atrophy. Emphasis is placed on the opposite direction of changes in the level of the highest-molecular-weight titin NT-isoforms in hibernating and non-hibernating mammals. Specifically, we discuss the maintenance of a constant level of titin NT-isoform in the muscles of hibernators, in contrast to a significant decrease in the level of NT-, as well as other (N2B-, N2BA-, and N2A-), isoforms of this protein in the muscles of non-hibernating animals and humans during the development of pathological changes. The described protective molecular mechanisms in the muscles of hibernators, absent in non-hibernating mammals and humans, contribute to the maintenance of a highly ordered sarcomeric structure and, consequently, the required level of muscle contractile activity during different phases of the hibernation season (entering hibernation, torpor, arousal from torpor, and interbout euthermia). The discussed molecular strategies of hibernating animals help prevent the development of pathological alterations in muscle tissue, ultimately contributing to the animal's survival under the harsh conditions of hibernation.