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bioRxiv · 10.64898/2026.09.28.755229

CONSTITUTIVE STIM1L DELETION ALTERS STORE-OPERATED CALCIUM ENTRY KINETICS BUT DOES NOT PERTURB THE DEVELOPMENT AND FUNCTION OF MOUSE SKELETAL MUSCLE

Dopont, O.·Lopez, G.·Lilliu, E.·Castets, P.·Koenig, X.·Frieden, M.·Koenig, S.
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Abstract

Store-operated calcium entry (SOCE) is a ubiquitous calcium (Ca2+) signalling mechanism that replenishes endoplasmic and sarcoplasmic reticulum Ca2+ stores. We previously identified STIM1L, a skeletal muscle-enriched STIM1 splice variant that enables rapid SOCE activation in human myotubes. To determine its physiological role in vivo, we generated a constitutive knockout mouse model that selectively abolishes STIM1L expression while preserving the canonical STIM1 isoform. Stim1l-KO mice developed normally and exhibited no overt abnormalities, but both sexes showed reduced voluntary wheel-running activity, suggesting neuromuscular perturbation. Skeletal muscle deprived of STIM1L did not show any histological alterations or changes in fibre- type and size. Likewise, force-frequency relationships and fatigue resistance measured ex vivo in isolated extensor digitorum longus and soleus muscles were indistinguishable from control muscles. This lack of difference may be explained by the increased expression of STIM1 in several skeletal muscles and suggests that changes in the voluntary running activity of Stim1l-KO mice may arise from STIM1L loss in non-muscular tissues, including the central nervous system. Notwithstanding, primary myotubes derived from Stim1l-KO mice displayed a marked delay in SOCE activation kinetics, whereas SOCE amplitude remained comparable to controls. This was consistent with a compensatory STIM1 upregulation maintaining overall Ca2+ entry capacity. Interestingly, electrically evoked Ca2+ transients in intact Stim1l-KO flexor digitorum brevis fibres exhibited significantly faster decay kinetics than controls. This revealed another role of STIM1L in Ca2+ handling in skeletal muscle that appears independent of its contribution to SOCE activation. Together, these findings establish STIM1L as a regulator of SOCE activation kinetics and indicate an additional role in myofibre Ca2+ clearance, while suggesting that compensatory upregulation of canonical STIM1 may preserve muscle structure and contractile function in its absence in mice.

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Dopont, O., Lopez, G., Lilliu, E., Castets, P., Koenig, X., Frieden, M., Koenig, S.. 2026-10-04. CONSTITUTIVE STIM1L DELETION ALTERS STORE-OPERATED CALCIUM ENTRY KINETICS BUT DOES NOT PERTURB THE DEVELOPMENT AND FUNCTION OF MOUSE SKELETAL MUSCLE. https://doi.org/10.64898/2026.09.28.755229

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