An age‐associated decline in the role of the sarcoplasmic reticulum and associated calcium‐handling proteins sets the pace for sinoatrial node function

With advancing age, the intrinsic function of the sinoatrial node (SAN) declines, as a result of structural changes and changes in electrical regulation within the constitutive cells of the nodal tissue. This study examined changes to proteins involved in regulating calcium flux balance in the atria and SAN of male rats used as a model of ageing throughout their lifespan at 6, 12 and 24 months of age. Using immunohistochemistry and western blotting, we determined a significant age-dependent decline in the levels of key calcium regulatory proteins within the SAN: Ca_v1.2, PMCA4, RYR2, SERCA2a and phospholamban (n = 5; ANOVA, P < 0.05). By contrast, levels of NCX protein were significantly elevated by 57.3% (P = 0.009) in the oldest group, indicating a potential pronounced change in calcium balance; a difference functionally observed by a steeper dose-response curve to the inhibitory effects of nifedipine. Intrinsic pacemaker beating rate was significantly reduced by 68 beats min^-1 in the oldest group compared to the youngest, (n = 6; ANOVA, P = 0.022). Negating sarcoplasmic reticulum calcium cycling and the 'calcium clock' using cyclopiazonic acid reduced the intrinsic pacemaker activity of the SAN in young animals to that observed in the oldest group. Under these conditions, spontaneous activity and the response of the SAN to isoprenaline became matched across all age groups. Restoring sarcoplasmic reticulum function to the SAN in the elderly may offer a route to combatting age-related suppression of function, although care should be taken in the use of calcium channel antagonists to avoid precipitating sick-sinus syndrome. KEY POINTS: This study adds understanding and characterisation of the age-dependent progressive reduction in sinoatrial node (SAN) function. We compared atria and the SAN across the lifespan of a Han Wistar rat model of ageing with animals studied at 6, 12 and 24 months of age. SAN tissue from old rats showed significantly reduced expression of key cellular calcium regulatory proteins compared to nodal tissue from young rats. The SAN from old rats exhibited a slowed intrinsic beating rate and an altered response to drugs that modulate cellular calcium handling. Eliminating sarcoplasmic reticulum calcium handling makes the SAN of a young animal mimic features of an aged animal.