A dual role for integrin‐linked kinase and β1‐integrin in modulating cardiac aging

Abstract

SUMMARY Cardiac performance decreases with age, which is a major risk factor for cardiovascular disease and mortality in the aging human population, but the molecular mechanisms underlying cardiac aging are still poorly understood. Investigating the role of Integrin-Linked Kinase (ilk) and β1-Integrin (myospheroid, mys) in Drosophila, which co-localize near cardiomyocyte contacts and Z-bands, we find that reduced ilk or mys function prevents the typical changes of cardiac aging seen in wildtype, such as arrhythmias. In particular, the characteristic increase in cardiac arrhythmias with age is prevented in ilk and mys heterozygous flies with nearly identical genetic background, and they live longer, in line with previous findings in C. elegans for ilk and Drosophila for mys. Consistent with these findings we observed elevated β1-integrin protein levels in old compared to young wild-type flies, and cardiac-specific overexpression of mys in young flies causes aging-like heart dysfunction. Moreover, moderate cardiac-specific knockdown of integrin/ILK pathway-associated genes also prevented the decline in cardiac performance with age. In contrast, strong cardiac knockdown of ilk or ILK-associated genes can severely compromise cardiac integrity, including cardiomyocyte adhesion and overall heart function. These data suggest that mys/ilk function is necessary for establishing and maintaining normal heart structure and function, and appropriate fine-tuning of this pathway can retard the age-dependent decline in cardiac performance, and extend lifespan. Thus, integrin/ILK-associated signaling emerges as an important and conserved genetic mechanism in longevity, and as a new means to improve age-dependent cardiac performance, in addition to its vital role in maintaining cardiac integrity.

Metabolism and successful aging: Polymorphic variation of syndecan-4 (SDC4) gene associate with longevity and lipid profile in healthy elderly Italian subjects

“…interactions and matrix-mediated cellular signaling cascades impacts the decline of age-dependent physiological performance and thereby life span (Goddeeris et al, 2003;Hansen et al, 2005;Wolfson et al, 2009;De Luca et al, 2010;De Luca et al, 2011;Wilson et al, 2013;Nishimura et al, 2014). Consistently, here we report that common genetic variants in the SDC4 gene affect human longevity.…”

Extracellular matrix downregulation in the Drosophila heart preserves contractile function and improves lifespan

“…Similarly, KD flies exhibited increased fractional shortening compared to controls (Figure 5C). Attenuation of other matrix-related pathways and presence of transgenic drivers has correlated with organismal lifespan extension [34, 39], and similarly we found that all maximum lifespans exceeded Hand- w 1118 controls with LanAKD flies living the longest at 39% longer (Supplemental Table S9, Figure 5D). …”

“…Hand- w 1118 control flies exhibited a significant reduction in diastolic and systolic dimensions with age [10, 34, 35] whereas PrcKD , LanAKD , or VkgKD flies did not (Figure 3, B and C). Combined with a basal increase in fly heart dimensions, PrcKD , LanAKD , and VkgKD flies exhibited improved fractional shortening with age while control flies did not (Figure 3D).…”

“…Moreover, flies can be exceedingly sensitive; here we have demonstrated that through direct measurement of transgenic flies where Laminin A, Viking, or Pericardin expression was moderately reduced we observed obvious improvements in age-related heart function. Similar sensitively is found throughout the fly heart; as β1-integrin signaling is reduced via heterozygous mutations to ILK or Mys (β1-integrin), cardiac tissue stiffening attenuates and lifespan is extended [34]. Conversely when cell-ECM signaling is excessive, it can alter myocyte coupling and stiffness, leading to functional deficits [45].…”

The (dys)functional extracellular matrix

“…Inhibiting FAK activity reduced resting and stretch-induced phosphorylation of ERK and integrin β 1 was required for stretch-induced phosphorylation of FAK [177]. Integrin β 1 may also be involved in age-related myocardial stiffening and diastolic diameter decrease [178]. …”