In a sense, exercise is damaging. It places stress on cells, but we have evolved to react to that stress and damage with greater maintenance, repair, and a shift of cell metabolism into a more beneficial state. That a mild or short term stress results in a long term benefit is called hormesis, and it is the case for near all forms of stress. There is a point at which any form of cellular stress or metabolic disarray tips over from net benefit to net harm, a dose-response curve that looks quite similar at the high level for cold, toxins, heat, lack of nutrients, exercise, and so forth. This remains the case once you move past the source of the stress and start picking apart the biochemical changes in cell activity and cell signaling generated in reaction to that stress.
Today's open access paper looks at HMGB1 in this context of stress and hormesis relating to exercise. HMGB1 is variously regarded as devil or angel in different scientific papers, and this does tend to be the case for many of the components of a stress response. HMGB1 can produce both benefits and harms, and the dose is everything when it comes to how the balance of outcomes affects health. So HMGB1 promotes cellular senescence in bystander cells when secreted by senescent cells as a part of the senescence-associated secretory phenotype, for example. But HMGB1 also reverses some losses of DNA structure in aged cells and increases stem cell activity to accelerate regeneration. This sort of characteristic can make stress response emulation a difficult class of therapy to bring to the clinic, as optimal doses (or even whether more versus less HMGB1 is beneficial!) might vary widely from species to species and from individual to individual within a species.
High mobility group box 1: DAMPening the danger molecule in cardiovascular disease with exercise
High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP). During cellular stress, it leaves the nucleus and moves into the extracellular space, where it modulates the development of cardiovascular diseases (CVDs), a leading global cause of age-related mortality. In preclinical models, administration of HMGB1-neutralizing antibodies increased the survival rates of lipopolysaccharide-treated mice by up to 30%, whereas treatment with recombinant HMGB1 was lethal. Furthermore, chronological aging is accompanied by a gradual increase in systemic HMGB1. Compared with young adults (18-30 years), older adults (≥70 years) have ∼ 25% higher serum HMGB1 concentrations. A longitudinal study also revealed an age-related increase in plasma HMGB1 from 3.5 ± 1.8 to 4.7 ± 1.5 ng/mL as participants aged from 24.6 ± 3.3 to 30.4 ± 3.4 years,4 suggesting that HMGB1 may reflect age-related inflammatory burden and contribute to the increased cardiovascular risk seen in older populations.
While evidence indicates that HMGB1 is associated with both the progression and severity of CVDs, it also has a paradoxically beneficial role in mitigating tissue repair. HMGB1 appears to have an important role in promoting stem cell recruitment and tissue regeneration. A role for HMGB1 in stem cell mobilization has been reported, wherein HMGB1 knockout mice exhibited impaired skeletal muscle regeneration following toxin-induced injury. In the same study, leukocyte-derived HMGB1 was required for the activation of satellite cells and vascularization in murine skeletal muscle.
Exercise training improves cardiovascular function and modulates systemic concentrations of HMGB1. Acute exercise induces the release of HMGB1 into systemic concentration, whereas long-term exercise training appears to reduce its systemic levels. This paradoxical response of HMGB1 to either short-term or chronic exercise, alongside its complex role in the pathogenesis of age-associated CVDs, makes it an intriguing subject for research. A potential explanation for this paradox may lie in HMGB1's capacity in regulating stem cell recruitment and tissue regeneration.
View the full article at FightAging
