Functional expression of transgenic α1sDHPR channels in adult mammalian skeletal muscle fibres

DiFranco, Marino; Tran, Philip; Quiñonez, Marbella; Vergara, Julio L.

doi:10.1113/jphysiol.2010.202804

Cited by 20 publications

(31 citation statements)

References 59 publications

(94 reference statements)

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“…STAC3-GFP localized in a repeating doublet pattern with the wider spaces correlating to the myosin heavy chains (Fig. 1D), consistent with a report describing in vivo localization of the T-tubule protein DHPR α1s to the borders of A bands (15). Using this technique, it is not possible to determine whether STAC3 localizes along the full length of the T tubules or more specifically to the triads.…”

Section: Resultssupporting

confidence: 68%

Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca ²⁺ release and contractility

Nelson

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

125

169

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Excitation-contraction (EC) coupling comprises events in muscle that convert electrical signals to Ca 2+ transients, which then trigger contraction of the sarcomere. Defects in these processes cause a spectrum of muscle diseases. We report that STAC3, a skeletal muscle-specific protein that localizes to T tubules, is essential for coupling membrane depolarization to Ca 2+ release from the sarcoplasmic reticulum (SR). Consequently, homozygous deletion of src homology 3 and cysteine rich domain 3 (Stac3) in mice results in complete paralysis and perinatal lethality with a range of musculoskeletal defects that reflect a blockade of EC coupling. Muscle contractility and Ca 2+ release from the SR of cultured myotubes from Stac3 mutant mice could be restored by application of 4-chloro-m-cresol, a ryanodine receptor agonist, indicating that the sarcomeres, SR Ca 2+ store, and ryanodine receptors are functional in Stac3 mutant skeletal muscle. These findings reveal a previously uncharacterized, but required, component of the EC coupling machinery of skeletal muscle and introduce a candidate for consideration in myopathic disorders.

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Section: Resultssupporting

confidence: 68%

Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca ²⁺ release and contractility

Nelson

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

125

169

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“…Whether the RyRs not directly associated with DHPRs contribute to Ca 2+ release is not clear (Dulhunty et al 2002) and increased DHPR content in the absence of increased RyR content could potentially lead to greater SR Ca 2+ release. While there are no previous reports showing that increased DHPR content results in increased force production, DiFranco et al (2011) showed that over‐expression of the DHPR α subunit in mouse muscle resulted in increased charge movement but this extra charge movement did not cause any extra Ca 2+ release. On the other hand, reductions in DHPR content have been shown to result in reduced force in skeletal muscle (Pietri‐Rouxel et al 2010).…”

Section: Discussionmentioning

confidence: 78%

Dietary nitrate increases tetanic [Ca²⁺]_i and contractile force in mouse fast‐twitch muscle

Hernández

Schiffer

Ivarsson

et al. 2012

The Journal of Physiology

268

349

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Key points Dietary supplementation with inorganic nitrate has beneficial effects on skeletal muscle responses to exercise. Both mitochondrial and extra‐mitochondrial explanations have been proposed. Contractile force of fast‐twitch muscles was enhanced in mice supplemented with 1 mm NaNO3 in drinking water for 7 days. Myoplasmic free [Ca2+] during tetanic stimulation was increased in fast‐twitch muscles of nitrate‐supplemented mice and this was accompanied by increased expression of calsequestrin 1 and the dihydropyridine receptor. These results provide a new mechanism by which nitrate exerts beneficial effects on muscle function with applications to sports performance and a potential therapeutic role in conditions with muscle weakness. Abstract Dietary inorganic nitrate has profound effects on health and physiological responses to exercise. Here, we examined if nitrate, in doses readily achievable via a normal diet, could improve Ca2+ handling and contractile function using fast‐ and slow‐twitch skeletal muscles from C57bl/6 male mice given 1 mm sodium nitrate in water for 7 days. Age matched controls were provided water without added nitrate. In fast‐twitch muscle fibres dissected from nitrate treated mice, myoplasmic free [Ca2+] was significantly greater than in Control fibres at stimulation frequencies from 20 to 150 Hz, which resulted in a major increase in contractile force at ≤50 Hz. At 100 Hz stimulation, the rate of force development was ∼35% faster in the nitrate group. These changes in nitrate treated mice were accompanied by increased expression of the Ca2+ handling proteins calsequestrin 1 and the dihydropyridine receptor. No changes in force or calsequestrin 1 and dihydropyridine receptor expression were measured in slow‐twitch muscles. In conclusion, these results show a striking effect of nitrate supplementation on intracellular Ca2+ handling in fast‐twitch muscle resulting in increased force production. A new mechanism is revealed by which nitrate can exert effects on muscle function with applications to performance and a potential therapeutic role in conditions with muscle weakness.

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“…However, the situation is in sharp contrast to what happens with the dihydropyridine receptor calcium channel (Cav1.1; DiFranco et al . ) and the sodium channel (Nav1.4; Capote et al . ) in which the expression of transgenic channels is made at the expense of a reduction of the native isoforms.…”

Section: Discussionmentioning

confidence: 99%

“…Data acquisition and conditioning was as previously described (DiFranco et al . ,b; DiFranco & Vergara, ). Unless indicated otherwise, data are presented as means ± SEM.…”

Section: Methodsmentioning

confidence: 99%

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Inward rectifier potassium currents in mammalian skeletal muscle fibres

DiFranco

Quiñonez

et al. 2015

The Journal of Physiology

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Key pointsr This paper provides a comprehensive electrophysiological characterization of the external [K + ] dependence and inward rectifying properties of Kir channels in fast skeletal muscle fibres of adult mice.r Two isoforms of inward rectifier K channels (IKir2.1 and IKir2.2) are expressed in both the surface and the transverse tubular system (TTS) membranes of these fibres.r Optical measurements demonstrate that Kir currents (IKir) affect the membrane potential changes in the TTS membranes, and result in a reduction in luminal [r A model of the muscle fibre assuming that functional Kir channels are equally distributed between the surface and TTS membranes accounts for both the electrophysiological and the optical data.r Model simulations demonstrate that the more than 70% of IKir arises from the TTS membranes.increases in the lumen of the TTS resulting from the activation of K delayed rectifier channels (Kv) lead to drastic enhancements of IKir, and to right-shifts in their reversal potential. These changes are predicted by the model. AbstractInward rectifying potassium (Kir) channels play a central role in maintaining the resting membrane potential of skeletal muscle fibres. Nevertheless their role has been poorly studied in mammalian muscles. Immunohistochemical and transgenic expression were used to assess the molecular identity and subcellular localization of Kir channel isoforms. We found that Kir2.1 and Kir2.2 channels were targeted to both the surface andthe transverse tubular system membrane (TTS) compartments and that both isoforms can be overexpressed up to 3-fold 2 weeks after transfection. Inward rectifying currents (IKir) had the canonical features of quasi-instantaneous activation, strong inward rectification, depended on the external [K + ], and could be blocked by Ba 2+ or Rb + . In addition, IKir records show notable decays during large 100 ms hyperpolarizing pulses. Most of these properties were recapitulated by model simulations of the electrical properties of the muscle fibre as long as Kir channels were assumed to be present in the TTS. The model also simultaneously predicted the characteristics of membrane potential changes of the TTS, as reported optically by a fluorescent potentiometric dye. The activation of IKir by large hyperpolarizations resulted in significant attenuation of the optical signals with respect to the expectation for equal magnitude depolarizations; blocking IKir with Ba 2+ (or Rb + ) eliminated this attenuation. The experimental data, including the kinetic properties of IKir and TTS voltage records, and the voltage dependence of peak IKir, while measured at widely dissimilar bulk [K + ] (96 and 24 mM), were closely predicted by assuming Kir permeability (PKir) values of ß5.5 × 10 −6 cm s −1 and equal distribution of Kir channels at the surface and TTS membranes. The decay of IKir records and the simultaneous increase in TTS voltage changes were mostly explained by K + depletion from the TTS lumen. Most importantly, aside from allowing an accurate estimation of mos...

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Functional expression of transgenic α1sDHPR channels in adult mammalian skeletal muscle fibres

Cited by 20 publications

References 59 publications

Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca ²⁺ release and contractility

Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca ²⁺ release and contractility

Dietary nitrate increases tetanic [Ca²⁺]_i and contractile force in mouse fast‐twitch muscle

Inward rectifier potassium currents in mammalian skeletal muscle fibres

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Functional expression of transgenic α1sDHPR channels in adult mammalian skeletal muscle fibres

Cited by 20 publications

References 59 publications

Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca 2+ release and contractility

Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca 2+ release and contractility

Dietary nitrate increases tetanic [Ca2+]i and contractile force in mouse fast‐twitch muscle

Inward rectifier potassium currents in mammalian skeletal muscle fibres

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Product

Resources

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Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca ²⁺ release and contractility

Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca ²⁺ release and contractility

Dietary nitrate increases tetanic [Ca²⁺]_i and contractile force in mouse fast‐twitch muscle