Disuse-induced Preferential Loss of the Giant Protein Titin Depresses Muscle Performance via Abnormal Sarcomeric Organization

Abstract

Persistent muscle weakness due to disuse-associated skeletal muscle atrophy limits the quality of life for patients with various diseases and individuals who are confi ned to bed. Fibers from disused muscle exhibit a marked reduction in active force production, which can exacerbate motor function, coupled with the well-known loss of muscle quantity. Despite recent understanding of the signaling pathways leading to the quantity loss, the molecular mechanisms of the depressed qualitative performance still remain elusive. Here we show that long-term disuse causes preferential loss of the giant sarcomere protein titin, associated with changes in physiologic muscle function. Ca 2+ sensitivity of active force decreased following 6 wk of hindlimb immobilization in the soleus muscle of the rat, accompanied by a shift in the length-active force relationship to the shorter length side. Our analyses revealed marked changes in the disused sarcomere, with shortening of thick and thin fi laments responsible for altered length dependence and expansion of interfi lament lattice spacing leading to a reduction in Ca 2+ sensitivity. These results provide a novel view that disuse-induced preferential titin loss results in altered muscle function via abnormal sarcomeric organization.

Diversity of human skeletal muscle in health and disease: Contribution of proteomics

“…RVE countermeasures appear to counteract the above described alterations by increasing troponin T and gelsolin. The disruption of the sarcomeric organization could also be the consequence of a loss of titin as observed in animal models [90]. The latter protein was not detected by the present analysis.…”

Physiological Functions of the Giant Elastic Protein Titin in Mammalian Striated Muscle

“…[88][89][90][91]). The recent work by Udaka et al [28] demonstrated that titin is reduced preferentially following long-term disuse, compared with other major sarcomere proteins, resulting in the disorganization of the ordered sarcomeric structure (Figs. 5 and 6).…”

“…Titin also plays an important role as a molecular scaffold for thick and presumably thin filament formation during myofibrillogenesis [23][24][25][26]. It is because of this scaffold-ing role that titin loss results in abnormal sarcomeric organization, as demonstrated in cell culture [27], and also in vivo with the disuse atrophy model [28].…”

Clinical definition and diagnostic criteria for sarcopenia

“…In our experiments on the effect of lattice spacing on reductions in contractile force, we found that improving lattice spacing significantly increased contractile force, although this was still less than that in healthy muscle. This suggests the presence of factors that regulate contractile force other than the muscular cross-sectional area and lattice spacing of filaments 35) .…”

“…The muscle fiber type is known to change during atrophy according to the causes that trigger the atrophy. For example, disuse muscular atrophy that arises according to the fixed-joint or dangling hind-leg model exhibits a decrease in type I fibers and an increase in type II fibers 34,35) . MyoD and HMGCoA-reductase inhibition have been suggested to participate in myosin 36,37) .…”