Bone: magnesium deficiency impairs 1α‑hydroxylase activity involved in 1,25‑dihydroxyvitamin D formation and can reduce bone extracellular fluid pH via reduced Mg-dependent proton pumps in periosteum and endosteum, contributing to demineralization and osteoporosis. [12
Muscle: experimental magnesium-deficient diets in mice alter expression of magnesium transport/homeostasis genes, modify fiber characteristics, and disturb pathways regulating muscle metabolism and contractility, even with relatively modest changes in serum magnesium. [26]
Connective tissue: low magnesium has been implicated in connective tissue dysplasia and impaired elastin/collagen integrity, consistent with its role in matrix metalloproteinases and cross-linking enzymes. [27]
From a systems perspective, bone and muscle are “deprioritized” under deficiency: they surrender magnesium to protect extracellular and critical organ pools, at the cost of gradual structural and functional decline. [6
Endocrine and metabolic cross‑talk in deficiency
Magnesium interacts tightly with hormonal networks that themselves reshape distribution and prioritization:
PTH and vitamin D: low Mg²⁺ stimulates PTH, which promotes bone resorption and renal reabsorption of both calcium and magnesium, but severe hypomagnesemia paradoxically impairs PTH secretion and action, leading to hypocalcemia and further neuromuscular instability. [8
Insulin: magnesium is a cofactor for the insulin receptor tyrosine kinase and many downstream kinases; deficiency promotes insulin resistance and alters glucose homeostasis, especially in adipose and muscle tissues. [15
RAAS and catecholamines: magnesium deficiency activates the renin–angiotensin–aldosterone system and stress hormones, further affecting vascular tone, cardiac workload, and renal electrolyte handling. [15
In adipose tissue, magnesium deficiency increases oxidative stress, mitochondrial dysfunction, and low‑grade inflammation, contributing to systemic metabolic dysfunction and potentially drawing magnesium into inflammatory and repair processes at the expense of long-term anabolic and storage functions. [15
Cellular responses to chronic insufficiency
Cell pathophysiology studies show that reducing extracellular magnesium leads to:
Growth arrest with accumulation in G0/G1 and reduced proliferation rates, minimizing DNA replication under suboptimal Mg²⁺ conditions and thereby protecting genomic integrity at the expense of regenerative capacity. [10
Altered mTOR signaling, where MgATP appears to regulate mTOR activity; decreased Mg²⁺ dampens mTOR-driven anabolic growth and protein synthesis, again biasing toward maintenance over growth. [10
Increased oxidative stress and inflammatory signaling, with Mg²⁺ deficiency favoring mitochondrial ROS production and cytokine release, which in turn may further damage magnesium-dependent enzymes and transporters, creating vicious cycles. [15
These adaptive responses represent a form of prioritization: core survival (membrane potential, minimal ATP production, basic repair) is maintained as long as possible, while cell division, growth, and high-demand synthetic functions are down‑regulated. [10
Clinical manifestations as a window into prioritization
The observable signs, symptoms, and clinical features of magnesium deficiency reflect the order in which systems fail:
Early or moderate deficiency: fatigue, anorexia, mild muscle weakness, and subtle neuropsychiatric symptoms, reflecting perturbations in ATP usage, neurotransmission, and muscle energetics before overt structural damage. [23
Progressive deficiency: muscle cramps, tremors, tetany, seizures, arrhythmias, and hypocalcemia/hypokalemia, indicating that membrane stability and ion homeostasis can no longer be maintained despite bone/muscle mobilization and renal conservation. [21
Chronic subclinical deficiency: hypertension, metabolic syndrome, type 2 diabetes, osteoporosis, and chronic inflammatory conditions, showing the long-term cost of prioritizing immediate excitability and ATP turnover over structural integrity, insulin sensitivity, and genomic stability. [7
These patterns align with a conceptual hierarchy:
Immediate survival (ATP generation, membrane potential, excitable tissue stability).
Core repair and immune competence (DNA repair, basic immunity, stress responses).
Growth, reproduction, and structural maintenance (bone, muscle quality, fine-tuned metabolic flexibility).
Integrative model of magnesium “triage”
Taken together, the literature supports a distributed “triage” model rather than a single control center, with prioritization emerging from:
Biophysical constraints: the necessity of MgATP for enzyme function and energy metabolism and the strong binding of magnesium to ATP and nucleic acids. [1
Transport topology: differential expression and regulation of TRPM6/7, MagT1, CNNMs, MRS2 and others in gut, kidney, heart, brain, immune cells, and muscle, producing tissue-specific resilience or vulnerability. [2
Buffering reservoirs: bone and muscle as large, semi‑labile stores whose mobilization protects critical pools but predisposes to structural disease over time. [4
Endocrine feedback: PTH, vitamin D, insulin, RAAS, and inflammatory cytokines that reshape fluxes and set the stage for chronic disease when deficiency persists. [8
During insufficiency, this system tends to:
Maintain extracellular ionized magnesium and intracellular MgATP in critical organs as long as possible. [1
Allow gradual depletion and dysfunction in slower-turnover tissues and in high-energy but non‑immediately‑lethal pathways (for example, bone remodeling, fine-tuned insulin signaling, long‑term genomic surveillance). [12
Ultimately fail in excitable tissues and hormone axes when buffering and conservation are exhausted, yielding the classic clinical syndromes of hypomagnesemia. [7