Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions

Abstract

Aging is an intricate process modulated by different molecular and cellular events, such as genome instability, epigenetic and transcriptional changes, molecular damage, cell death and senescence, inflammation, and metabolic dysfunction. Particularly, protein quality control (chaperone systems) tends to be negatively affected by aging, thus leading to cellular senescence in metabolic tissues and, as a consequence, to the increasing dissemination of inflammation throughout the body. The heat shock (HS) response and its associated expression of the 70 kDa family of heat shock proteins (HSP70), which are anti-inflammatory molecular chaperones, are found to be markedly decreased during muscle inactivity and aging, while evidence supports the loss of HSP70 as a key mechanism which may drive muscle atrophy, contractile dysfunction, and reduced regenerative capacity. In addition, abnormal stress response is linked with higher incidence of neurodegenerative diseases as well as low-grade inflammatory diseases that are associated with physical inactivity and obesity. Therefore, strategies to increase or, at least, to maintain the levels of HSP70, and its accompanying HS response to stress, are key to reduce biological cell dysfunctions that occur in aging. In this sense, physical exercise is of note as it is the most powerful inducer of the HS response, comparable only to heat stress and fever-like conditions. On the other hand, the amino acid L-glutamine, whose production within the skeletal muscle and liberation into the blood stream is dependent on muscle activity, is a potentializer of HSP70 expression and HS response, particularly via its entering in hexosamine biosynthetic pathway (HBP). Herein, we discuss the collaborative role of glutamine (and its donors/precursors) and physical exercise (mostly responsible for glutamine release into the circulation) as potential tools to increase HSP70 expression and the HS response in the elderly.

Acute exercise boosts cell proliferation and the heat shock response in lymphocytes: correlation with cytokine production and extracellular-to-intracellular HSP70 ratio

“…Consequently, the ratio between eHSP70 and iHSP70 (R = [eHSP70]/[iHSP70]) correlates with organismal immunoinflammatory balance, whereas the rate of variation in R ratios between different conditions (a.k.a. H-index of HSP70 status) is regarded as an index of changes in overall immunoinflammatory balance (Krause et al 2015a(Krause et al , 2015bLeite et al 2016;Schöler et al 2016;Krause and Rodrigues-Krause 2011). Therefore, in the present study, we investigated, in the rat model, whether acute exercise bouts of different intensities could influence the HS response of lymphocytes, which are a main source of both eHSP70 and iHSP70 under stressful situations (Hunter-Lavin et al 2004;Ireland et al 2007).…”

“…the biochemical pathway centred mainly on heat shock transcription factor-1 (HSF1)-dependent activation of HSP70 expression (Lindquist 1986;Anckar and Sistonen 2011), works to protect thermally damaged proteins from aggregation as well as to unfold aggregated proteins and to refold damaged proteins or target them for efficient degradation (Verghese et al 2012). This maintains intracellular protein homeostasis (proteostasis), thus avoiding the formation of toxic polypeptide aggregates that may trigger apoptosis or inflammation (Newsholme and Homem de Bittencourt 2014;Leite et al 2016). The HS response evolved to adapt organisms appropriately against several stressful insults, whether from heat, cold, oxidation, free radicals, toxins, hypoxia or metabolic stresses, including exercise (Hooper et al 2014).…”

“…The HS response evolved to adapt organisms appropriately against several stressful insults, whether from heat, cold, oxidation, free radicals, toxins, hypoxia or metabolic stresses, including exercise (Hooper et al 2014). Indeed, exercise, which is a strong homeostasis-threatening challenge, is one of the most powerful inducers of intracellular HSP70 (iHSP70) expression and HS response, comparable only to heat stress (Newsholme et al 2009;Heck et al 2011;Krause et al 2015b;Leite et al 2016). Moreover, HS response is also recruited from other branches of metabolism very far from proteostasis, at least a priori.…”

“…This is the case of inflammation, energy preservation and immune responses (Newsholme and Homem de Bittencourt 2014). Importantly, by hampering the activation of nuclear transcription factors of the kappa light chain enhancer of activated B cells (κB) family (NF-κB), at multiple regulatory levels, the HS response is antiinflammatory in its very essence (Leite et al 2016).…”

“…Impaired HS response, on the other hand, is a common feature of several chronic degenerative conditions associated with unresolved inflammation, such as cardiovascular diseases (CVD), obesity, type 1 (T1DM) and type 2 diabetes mellitus (T2DM), ageing and neurodegenerative diseases (Di Naso et al 2015;Hooper et al 2014;Krause et al 2014aKrause et al , 2014b; Krause and Homem de Bittencourt 2008;Leite et al 2016). Although suppression of HSF1 expression associated with decreased amounts of iHSP70 is a hallmark of chronic inflammatory diseases (Chung et al 2008;Rodrigues-Krause et al 2012;Di Naso et al 2015; Newsholme and Homem de Bittencourt 2014; Krause et al 2015aKrause et al , 2015b, iHSP70 levels, per se, are not the main issue; the impairment in tissue capacity to trigger a robust HS response in reaction to homeostatic challenges is the real problem.…”