STIM1 Reduction Prevents Tubular Aggregate Formation and Compromises Muscle Performance in Ageing Mice

Ageing is an irreversible process involving the gradual decline of cellular functions in all tissues. In male mice, age-related loss of muscle force is accompanied by the formation of tubular aggregates, which are honeycomb-like structures composed of membrane tubules, proteins and Ca²⁺ deposits. Tubular aggregates are also found in tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two clinically overlapping human disorders affecting skeletal muscle, bones, skin, spleen and platelets. TAM/STRMK is caused by gain-of-function mutations in the ubiquitously expressed Ca²⁺ sensor STIM1 and results in excessive extracellular Ca²⁺ entry and the dysregulation of Ca²⁺ homeostasis.

To understand the correlation between ageing, tubular aggregate formation, Ca²⁺ and STIM1, we conducted comparative analyses of WT and Stim1^+/- male mice until 18 months of age. We examined growth, general and specific muscle force, fatigability and muscle structure.

Stim1^+/- mice were born with the expected Mendelian ratio and showed unremarkable postnatal development with normal body and organ weight. However, at 18 months, Stim1^+/- mice manifested delayed muscle contraction (Δ = 28%, p < 0.05) and relaxation (Δ = 40%, p < 0.01) kinetics as well as exacerbated fatigue (Δ = 28%, p < 0.05) compared with age-matched controls. Morphological investigations of Stim1^+/- muscle sections by light and electron microscopy uncovered a shift towards slow myofibres and mitochondrial proliferation accompanied by enhanced SDH activity (Δ = 27%, p < 0.0001), an almost twofold increase in ROS production (p < 0.05), and signs of mitophagy-all representing histopathological hallmarks of age-related deterioration of muscle function known as sarcopenia. Strikingly, tubular aggregates-though abundant in WT muscles at 18 months-were absent in Stim1^+/- mice.

Taken together, STIM1 depletion by 50% had no discernible effect on muscle function in young adult male mice, but compromised muscle performance and resistance to fatigue at later life stages. These findings highlight a critical role of STIM1 and Ca²⁺ balance in the maintenance of muscle physiology, fibre type composition and mitochondrial bioenergetics. The absence of tubular aggregates in Stim1^+/- mice indicates that tubular aggregates possibly play a protective role and may contribute to the prevention of age-related muscle alterations.