Utrophin suppresses low frequency oscillations and coupled gating of mechanosensitive ion channels in dystrophic skeletal muscle

Abstract

A n absence of utrophin in muscle from mdx mice prolongs the open time of single mechanosensitive channels. On a time scale much longer than the duration of individual channel activations, genetic depletion of utrophin produces low frequency oscillations of channel open probability. Oscillatory channel opening occurred in the dystrophin/utrophin mutants, but was absent in wild-type and mdx fibers. By contrast, small conductance channels showed random gating behavior when present in the same patch. Applying a negative pressure to a patch on a DKO fiber produced a burst of mode II activity, but channels subsequently closed and remained silent for tens of seconds during the maintained pressure stimulus. In addition, simultaneous opening of multiple MS channels could be frequently observed in recordings from patches on DKO fibers, but only rarely in wild-type and mdx muscle. A model which accounts for the singlechannel data is proposed in which utrophin acts as gating spring which maintains the mechanical stability a caveolar-like compartment. The state of this compartment is suggested to be dynamic; its continuity with the extracellular surface varying over seconds to minutes. Loss of the mechanical stability of this compartment contributes to pathogenic Ca 2C entry through MS channels in Duchenne dystrophy.

The Pump-Leak/Donnan ion homeostasis strategies of skeletal muscle fibers and neurons

“…A precedent is worth recalling here: Aplysia neurons’ serotonin and arachidonic acid regulated resting K + -channels (Belardetti et al 1986) are adventitiously mechanosensitive (e.g., see Vandorpe et al 1994; Morris and Horn 1991; Methfessel et al 1986; Zhang and Hamill, 2000; Zhang et al 2000; Morris 2012). Likewise for SMF mechanosensitive cation channels, but decades on, they have no attributed function (Lansman 2015; Suchyna 2017). A hypothesis worth pursuing: this cation channel does for SMFs what NALCN does for smooth muscle (e.g.…”

Donnan dominated ion homeostasis and the longevity of ischemic Na+-loaded dystrophic skeletal muscle

“…No NALCN is detected in SMFs, but other cation channels (Metzger et al 2020) might contribute to P Na and if over-active, they would be problematic. In mdx fibers, over-active mechanosensitive cation channels (unidentified) and AChRs are posited routes for pathological Ca 2+ -entry (Franco and Lansman 1990; Carlson and Officer 1996; Yeung et al 2005; Lansman 2015; Ward et al 2018). If so, unavoidably, they are also “Na + -leaks”.…”

“…In mdx muscles, electromyography of abnormal spontaneous potentials and complex repetitive discharges resemble the muscle discharges of boys with DMD (Carter et al 1992; Han et al 2006). Where there is Nav-CLS-induced hypersensitivity, erratic myogenic APs bouts are expected if the damaged dystrophic sarcolemma also has leaky” cation-channels that activate intermittently, depolarizing Vm (Lansman 2015; and see next section).…”

“…For three minimal P-L/D models (Donnan dominated SM-CD and LA-CD, and Pump-Leak dominated WD-CD), the P-L/D processes are plotted during an identical 4 min step-activation (then step-deactivation) of cation channels (see Equation 4 ). (The on/off would apply if, as suggested by (Lansman 2015), these were mechanosensitive channels rendered hypermechanosensitive (Vandorpe et al 1994) in DMD-damaged sarcolemma, experiencing transient localized membrane stretch. If, more simply, damage induced an open probability increase, there would be an on-step only.)…”

“…2. Malfunctioning pumps in blebdamaged sarcolemma that accumulates because DMD fibers’ regenerative capabilities are impaired (Chang et al 2016; Shattock & Matsuura 1993; Williams and Bloch, 1999; Whitehead et al 2010; Juel et al 2015; Lansman 2015; Burr and Molkentin 2015; McElhanon & Bhattacharya 2018; Murphy et al 2019). 3.…”