In this issue, Arimura et al. (Hum Mutat 32: 1481–1491, 2011) report novel insights into the disease mechanisms linking together the co-chaperone BAG3 with dilated cardiomyopathy (DCM), a frequently fatal heart disease ultimately requiring heart transplantation. BAG3 is incorporated into mature cardiac myocytes within the sarcomeric Z-disk and is thought to fulfill co-chaperone functions by regulating HSP70. The Z-disk is a densely packed protein lattice that structurally integrates thin filaments from opposite sarcomeres cross-linked by alpha-actinin and a multitude of regulatory proteins (such as BAG3). Because of these features, Z-disks are perfectly positioned to sense sarcomeric strain and to generate trophic signals inside myocytes.
Consistent with the concept that Z-disks act as biomechanically active signalosomes, an increasing number of mutations associated with heart diseases have been identified among its components. Recent studies identified BAG3 mutations in DCM (Norton et al., Am J Hum Genet 88:273, 2011; Villard et al., Eur Heart J 32:1065, 2011). Kimura and colleagues now report two additional BAG3 mutations from two independent Japanese families. The mutated BAG3, when being expressed in neonatal rat cardiac myocytes, was found to impair Z-disk structures, and cardiac myocytes expressing mutated BAG3 were more vulnerable to enhanced apoptosis under conditions of serum deprivation and doxorubicin treatment. Therefore, the BAG3/Z-disk complex appears to be a novel player in the regulation of cardiomyocyte survival.
Their discoverya begs the question of whether BAG3/HSP70 activities can be regulated inside Z-disks biomechanically, and if differences in life-style and activity could explain the great variability of disease manifestation in BAG3-associated DCM. BAG3-associated signals from the Z-disk may also be involved in the pathophysiology of other forms of heart failure or in skeletal muscle disorders, such as myofibrillar myopathy.