The determinants of transverse tubular volume in resting skeletal muscle

Key points The surface membrane of skeletal muscle infolds to form a system of transverse (t)‐tubules, which propagate electrical activity deep into the fibre to activate muscle contraction. Ionic currents flowing into and out of the t‐tubules can cause osmotic fluxes and tubular volume changes, such as those seen in muscle fatigue and trauma, but the mechanisms driving these are unclear. We used a computer model to determine that resting t‐tubule volume is maintained by active ion cycling between the extracellular fluid, muscle cell and t‐tubules. By considering how these ion cycles are influenced by the extracellular fluid composition, we can reliably predict the resultant changes in t‐tubule volume. These findings explain and reconcile previous experimental data, providing a framework for understanding the role of the t‐system in muscle physiology and pathology.Abstract The transverse tubular (t)‐system of skeletal muscle couples sarcolemmal electrical excitation with contraction deep within the fibre. Exercise, pathology and the composition of the extracellular fluid (ECF) can alter t‐system volume (t‐volume). T‐volume changes are thought to contribute to fatigue, rhabdomyolysis and disruption of excitation–contraction coupling. However, mechanisms that underlie t‐volume changes are poorly understood. A multicompartment, history‐independent computer model of rat skeletal muscle was developed to define the minimum conditions for t‐volume stability. It was found that the t‐system tends to swell due to net ionic fluxes from the ECF across the access resistance. However, a stable t‐volume is possible when this is offset by a net efflux from the t‐system to the cell and thence to the ECF, forming a net ion cycle ECF→t‐system→sarcoplasm→ECF that ultimately depends on Na + /K + ‐ATPase activity. Membrane properties that maximize this circuit flux decrease t‐volume, including P Na(t)  >  P Na(s) , P K(t)  <  P K(s) and N (t)  <  N (s) [ P , permeability; N , Na + /K + ‐ATPase density; ( t ), t‐system membrane; ( s ), sarcolemma]. Hydrostatic pressures, fixed charges and/or osmoles in the t‐system can influence the magnitude of t‐volume changes that result from alterations in this circuit flux. Using a parameter set derived from literature values where possible, this novel theory of t‐volume was tested against data from previous experiments where t‐volume was measured during manipulations of ECF composition. Predicted t‐volume changes correlated satisfactorily. The present work provides a robust, unifying theoretical framework for understanding the determinants of t‐volume.