Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity

Abstract

Background: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial. Methods: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well. Results: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity. Conclusions: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.

Letter by Xie and Hou Regarding Article, “Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity”

“…2,3 Given the healthy heart function of midlife wild-type mice, autophagy in cardiomyocytes should be normal. However, inconsistent results were obtained in the study by Abdullatif et al 1 ; for example, the autophagic flux of the 12-month-old wild-type mice was not impaired (Figure 2G and 2H), but the 11-month-old wild-type mice showed blocked autophagic flux (Figure S10A and S10B). 1…”

Monoamine Oxidase-Dependent Pro-Survival Signaling in Diabetic Hearts Is Mediated by miRNAs

“…These apparently contradictory findings can be reconciled by examining the role of IGF1R in young vs. old mice. IGF1R activation increases cardiac contractility and function in young mice, but it can be detrimental in old mice leading to an impairment in the autophagy flux and oxidative phosphorylation in the heart [ 65 ]. Regardless of age, numerous studies showed that promoting IGF1R-dependent anti-apoptotic signaling is cardioprotective in pathological conditions, such as doxorubicin-induced cardiotoxicity or myocardial infarction [ 66 , 67 , 68 ].…”

Autophagy in striated muscle diseases

“…G protein-coupled receptor kinase 4 (GRK4) aggravates cardiomyocyte injury during myocardial infarction (MI) by inhibiting histone deacetylase 4 (HDAC4)-mediated Beclin-1 transcription, while MI-induced cardiac dysfunction and remodeling are improved by deleting cardiomyocytespecific GRK4 (30). Moreover, other regulatory factors of autophagy, including KAT8 Regulatory NSL complex subunit 1 (KANSL1) (31), Lysosome-associated membrane protein 2 (LAMP2) (32)(33)(34), insulin-like growth factor 1 receptor (IGF1R) (35) and HDAC (36,37), also play imperative roles in maintaining cardiac fitness, and their abnormality leads to heart diseases. These findings demonstrate that autophagy is important for cardiac function.…”