TRiC/CCT chaperonins are essential for maintaining myofibril organization, cardiac physiological rhythm, and lifespan

Abstract

We recently reported that CCT chaperonin subunits are upregulated in a cardiac-specific manner under time-restricted feeding (TRF) (Gill et al. Science 2015, 347:1265–9), suggesting that TRiC/CCT has a heart-specific function. To understand the CCT chaperonin function in cardiomyocytes, we performed its cardiac-specific knock-down in the Drosophila melanogaster model. This resulted in disorganization of cardiac actin- and myosin-containing myofibrils and severe physiological dysfunction, including restricted heart diameters, elevated cardiac dysrhythmia and compromised cardiac performance. We also noted that cardiac-specific knock-down of CCT chaperonin significantly shortens lifespans. Additionally, disruption of circadian rhythm yields further deterioration of cardiac function of hypomorphic CCT mutants. Our analysis reveals that both the orchestration of protein folding and circadian rhythms mediated by CCT chaperonin are critical for maintaining heart contractility.

Time-restricted feeding restores muscle function in Drosophila models of obesity and circadian-rhythm disruption

“…It is estimated that ~20% of the US workforce is exposed to abnormal light conditions due to shiftwork 44,45 , which is known to compromise cardiometabolic fitness. We have shown that light-induced circadian disruption compromises cardiac performance 46 . To evaluate the impact of TRF on skeletal muscle function when circadian rhythms were disrupted by light, we placed flies ( Canton-S , w 1118 , or SK2 mutants) in constant light (LL) and fed them RD under ALF or TRF conditions (Fig.…”

“…One-day-old wild-type and obese flies were collected and kept at 22 °C, 50% humidity in a 12 h light/12 h dark (LD) cycle 10 . Alternatively, flies were maintained in constant light conditions (LL) 46 . Adult flies were collected upon eclosion, separated by sex, and maintained on a standard diet in groups of 20–25 for 3 days.…”

“…The remaining statistical test (5d, f, g, and i red asterisks only; 8i and 8j) used ANOVA with post ad hoc Sidak’s method with multiple comparisons. All tests performed were done using GraphPad Prism 6 10,14,46 . Bar graphs show mean and standard deviation (SD), written as mean ± SD, with significance presented as * p < 0.05, ** p < 0.01, *** p < 0.001.…”

Mitochondrial stress management: a dynamic journey

“…Nuclear magnetic resonance (NMR), crosslinking-mass spectrometry and modeling approaches suggest that recognition codes in the polypeptide enable substrate recognition by TRiC 137. Significantly, TRiC chaperonins have been linked to numerous pathologies, such as neuropathies 138, oncogenesis 139, or age-related diseases 140141. A connection between the cytosolic UPR and mitochondrial function has recently been described by means of the heat shock factor 1 (HSF1), which is a quality control regulator with a role in systemic energy sensing and metabolic adaptation to nutrient availability 142.…”

Role of Autophagy in Proteostasis: Friend and Foe in Cardiac Diseases

“…In response to proteotoxic stress in the cytosol, the HSR is activated. The HSR acts as the cell’s frontline system to safeguard the folding and trafficking of functional proteins by means of chaperones, including heat shock proteins (HSPs) and chaperonins (such as T-complex protein 1 ring complex [TRiC], HSPB1, HSPB5, HSPB6, HSPB7, and HSPB8), which are highly expressed in the heart [8,9,10]. Proteotoxic stress in the endoplasmic reticulum (ER) may lead to activation of the UPR, which prevents protein aggregation and guarantees correct protein folding.…”