Abstract <p>The review presents data on the features of protein homeostasis(proteostasis) of the giant sarcomeric cytoskeletal proteins titinand nebulin in hibernating animals during the development of atrophicchanges in skeletal muscles and the hypertrophic response in thecardiac muscle during hibernation. Maintenance of stable titin andnebulin levels results from two molecular strategies: (1) inhibitionof proteolysis of the giant proteins during torpor; (2) preferentialsynthesis of titin and nebulin during periods of winter euthermia,accompanied by the renewal of these proteins and restoration ofthe quantitative content of titin reduced during hypothermia. Dataare presented on the decreased quantitative content of titin andnebulin in the muscles of non-hibernating animals, as well as humans,during the development of a number of pathological processes, includinghypertrophic cardiomyopathy and skeletal muscle atrophy. Emphasisis placed on the opposite direction of changes in the level of thehighest-molecular-weight titin NT-isoforms in hibernating and non-hibernatingmammals. Specifically, we discuss the maintenance of a constantlevel of titin NT-isoform in the muscles of hibernators, in contrastto a significant decrease in the level of NT-, as well as other(N2B-, N2BA-, and N2A-), isoforms of this protein in the musclesof non-hibernating animals and humans during the development ofpathological changes. The described protective molecular mechanismsin the muscles of hibernators, absent in non-hibernating mammalsand humans, contribute to the maintenance of a highly ordered sarcomericstructure and, consequently, the required level of muscle contractileactivity during different phases of the hibernation season (enteringhibernation, torpor, arousal from torpor, and interbout euthermia).The discussed molecular strategies of hibernating animals help preventthe development of pathological alterations in muscle tissue, ultimatelycontributing to the animal's survival under the harsh conditionsof hibernation.</p>