Body Mass Scaling of Sodium Regulation in Mammals

Sodium (Na⁺) supports metabolic, neural, and muscular functions, and plays a critical role in fluid volume and blood pressure homeostasis. For many wild mammals, inadequate Na⁺ intake can lead to hyponatremia, where low Na⁺ levels disrupt fluid balance and may cause seizures or death [1]. Conversely, chronic excess in Na⁺ intake, common in both humans and domestic animals, may increase blood pressure and elevate the risk of cardiovascular disease and premature death [2]. Nevertheless, there remains considerable debate regarding the mechanisms of Na⁺ balance and why some individuals exhibit greater Na⁺ sensitivity [3].

Mammals, including humans, assimilate most (> 90%) of their dietary Na⁺ into the bloodstream [4]. Consequently, elevated Na⁺ consumption can quickly raise blood Na⁺ levels above the narrow limits required to maintain osmotic balance and blood pressure. To prevent this, mammals have evolved a number of mechanisms for regulating excess Na⁺ from the body [4]. The primary pathway is renal excretion of Na⁺ in urine [1, 3]. A secondary mechanism involves secretion of Na⁺ from the bloodstream into the large intestine for elimination in feces, though this is typically an order of magnitude smaller [4]. Third, mammals have evolved a specialized mechanism for buffering excess Na⁺ in the bloodstream: the temporary storage of Na⁺ in extrarenal body tissues [5].

The idea that mammals can store excess Na⁺ originated in the early 1900s, but more contemporary work by Titze and colleagues has shifted the paradigm regarding how the body handles excess Na [5, 6]. Traditionally, it was believed that increased Na⁺ intake required proportional increases in water to maintain extracellular osmolarity, while the kidneys excreted surplus Na⁺ to restore Na⁺ balance. However, recent evidence suggests that Na⁺ can be stored in extrarenal body tissues without commensurate water retention [5]. Most research has identified skin and muscle as the primary sites of Na storage, where Na⁺ binds to negatively charged glycosaminoglycans (GAGs) [5]. However, bone contains ~45% of total body Na, and while only one third of this Na⁺ is thought to be readily exchangeable [3], this would represent a substantial component of the body's short-term Na storage capacity. Still, the magnitude and dynamics of extrarenal Na⁺ storage remain poorly understood, with inconsistencies among species and individuals. For example, a study on dogs showed no signs of extrarenal Na⁺ storage [7], while others suggested that Na⁺ associated with GAGs remains osmotically active and excess Na⁺ storage simply reflects extracellular volume expansion [8].

Here, we hypothesize that the regulation of extrarenal Na⁺ storage may be influenced by a universal yet understudied factor: body mass (BM; Figure 1). When examining the maximal rate of Na⁺ filtration and excretion in kidneys, we find that this is primarily governed by metabolic processes that scale hypoallometrically at ~BM^0.75 (Figure 1a). In contrast, the mass of key Na⁺ storage tissues, including skin (BM^{0.97 (95% CI: 0.96–0.98)}; Wada et al. [9]; Figure 1b), muscle (BM^{1.01 (95% CI: 0.99–1.03)}; Muchlinski et al. [10], Figure 1c), and bone (BM^{1.10 (95% CI: 1.08–1.12)}; Prange et al. [11]; Figure 1d), scale isometrically or hyperallometrically. These scaling differences suggest that larger mammals may possess a higher capacity for extrarenal storage as compared to their renal excretion potential (Figure 1e).

The potentially greater ability of larger animals to store excess Na⁺ in body tissues has important physiological, ecological, and medical implications. Notably, it suggests that larger mammals may be better equipped to buffer short-term spikes in Na intake, potentially reducing their susceptibility to hypertension. Conversely, new research by Duvall et al. [12] highlighted that large mammals may also be more vulnerable to Na⁺ deficiency due to discrepancies in the allometric scaling of Na⁺ intake (BM^0.71–0.79) and Na⁺ requirements (BM^{0.91 (CI: 0.80–1.0)}). Accordingly, for animals facing Na scarcity, larger species may have a greater capacity to retain Na in tissues, helping to extend the benefits of infrequent Na access, such as through the ingestion of Na-rich soil at salt licks [12].

While studies of Na⁺ homeostasis and regulation often rely on small animal models (typically rodents), such experiments may not elicit the same physiological responses as those in humans and other larger mammals. For example, using livestock or zoo animals has the distinct advantage of examining similarly sized organs and functions as human subjects. Today, hypertension remains a widespread medical condition throughout modern societies [3]. An improved understanding of Na⁺ balance and storage across mammalian body sizes may help inform medical treatments and public communication strategies, as well as unlock important considerations for domestic and wild animal management.

The authors declare no conflicts of interest.