The proposed titin organization in the sarcomeric I-band under normal and stress conditions and the protective effects of sHSPs. (A) Elastic titin filaments normally traverse the I-band in a monomeric state, except in the distal Ig region where they form hexamers (Houmeida et al., 2008). (B) Unfolding of I-band Ig domains together with acidic stress may cause increases in titin aggregation and myocyte stiffness. The mechanically more stable, self-associating, distal Ig domains likely do not unfold. Intrinsically disordered titin regions (N2-Bus and PEVK) do not aggregate. (C) Association of sHSPs with unfolded Ig domains in a region between the Z-disk–I-band junction and PEVK protects against titin aggregation and helps prevent abnormal myocyte stiffening.