Age-Dependent Effects of Muscle Resting Calcium on Fasting Blood Glucose: Implications for Prediabetes Risk

Skeletal muscle is the primary site for insulin-mediated glucose uptake and is critical in maintaining whole-body glucose homeostasis. Muscle cells from malignant hyperthermia-susceptible (MHS) individuals exhibit elevated resting cytosolic calcium concentration ([Ca²⁺]_cyto), and MHS subjects have a higher incidence of hyperglycaemia. This study investigates the association between elevated resting [Ca²⁺]_cyto and fasting blood sugar (FBS) levels while accounting for subject demographics and clinical variables.

We measured resting [Ca²⁺]_cyto in myotubes derived from muscle biopsies of control and MHS subjects. We analysed the impact of [Ca²⁺]_cyto on FBS levels based on age, sex, and MH status through correlation and comparative analyses. Data were stratified by FBS, [Ca²⁺]_cyto, and age, and heat map and 3D mesh plot analyses were performed to assess the risk of prediabetes in subjects with varying [Ca²⁺]_cyto and age.

Between 2013 and 2024, muscle biopsies from 152 subjects (90 MHS, 62 controls) were used to establish primary myotube culture. MHS myotubes exhibited significantly higher resting [Ca²⁺]_cyto than controls and [Ca²⁺]_cyto positively correlated with fasting blood sugar (FBS) in MHS subjects (r = 0.227; p = 0.031) and across the entire cohort (r = 0.176; p = 0.034). This correlation was high in prediabetic individuals (r = 0.43; p = 0.005) but absent in those with normal FBS. Subjects over 40 years with [Ca²⁺]_cyto > 150 nM showed a higher risk of prediabetes. While aging is a significant risk factor for type 2 diabetes, increased age did not impact FBS levels in individuals with [Ca²⁺]_cyto below 150 nM. However, in those with [Ca²⁺]_cyto exceeding 150 nM, increasing age significantly influenced FBS.

Elevated resting [Ca²⁺]_cyto in skeletal muscle amplifies the risk of hyperglycemia and may contribute to the onset of type 2 diabetes.