The skeletal muscle and myocardial cells present highly specialized structures; for example, the close interaction between the sarcoplasmic reticulum (SR) and mitochondria—responsible for excitation-metabolism coupling—and the junction that connects the SR with T-tubules, critical for excitation-contraction (EC) coupling. The mechanisms that underlie EC coupling in these two cell types, however, are fundamentally distinct. They involve the differential expression of Ca2+ channel subtypes: CaV1.1 and RyR1 (skeletal), vs. CaV1.2 and RyR2 (cardiac). The CaV channels transform action potentials into elevations of cytosolic Ca2+, by activating RyRs and thus promoting SR Ca2+ release. The high levels of Ca2+, in turn, stimulate not only the contractile machinery but also the generation of mitochondrial reactive oxygen species (ROS). This forward signaling is reciprocally regulated by the following feedback mechanisms: Ca2+-dependent inactivation (of Ca2+ channels), the recruitment of Na+/Ca2+ exchanger activity, and oxidative changes in ion channels and transporters. Here, we summarize both well-established concepts and recent advances that have contributed to a better understanding of the molecular mechanisms involved in this bidirectional signaling.

Oculopharyngeal muscular dystrophy (OPMD) is linked to mutations in the gene encoding poly(A)-binding protein nuclear 1 (PABPN1). OPMD mutations consist of an expansion of a tract that contains 10 alanines (to 12-17). This disease courses with muscle weakness that begins in adulthood, but the underlying mechanism is unclear. In the present study, we investigated the functional effects of PABPN1 and an OPMD mutation (PABPN1-17A) using myotubes transfected with cDNAs encoding these proteins (GFP-tagged). PABPN1 stimulated myoblast fusion (100%), whereas PABPN1-17A failed to mimic this effect. Additionally, the OPMD mutation markedly altered nuclear morphology; specifically, it led to nuclei with a more convoluted and ovoid shape. Although PABPN1 and PABPN1-17A modified the expression of sarcoplasmic/endoplasmic reticulum Ca -ATPase and calsequestrin, the corresponding changes did not have a clear impact on [Ca ]. Interestingly, neither L-type Ca channels, nor voltage-gated sarcoplasmic reticulum (SR) Ca release (VGCR) was altered by PABPN1. However, PABPN1-17A produced a selective inhibition of VGCR (50%). This effect probably arises from both lower expression of RyR1 and depletion of SR Ca . The latter, however, was not related to inhibition of store-operated Ca entry. Both PABPN1 constructs promoted a moderated decrease in cytosolic [Ca ], which apparently results from down-regulation of excitation-coupled Ca entry. On the other hand, PABPN1-17A did not alter ECC in muscle fibres, suggesting that adult muscle is less prone to developing deleterious effects. These results demonstrate that PABPN1 proteins regulate essential processes during myotube formation and support the notion that OPMD involves disruption of myogenesis, nuclear structure and homeostasis of Ca .

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Our previous work investigated the role of aldosterone in the function of atrial myocytes. Among other effects, aldosterone promoted a striking 2-fold increase in the density of Ca 2þ current (I Ca ) and a moderated increase of 30% in cell membrane capacitance (C m , suggesting hypertrophy). Ca 2þ and ROS were identified to participate but only on the effect on C m . The objective of this work was twofold: (a) to determine whether aldosterone regulates ROS generation; and (b) to reexamine the potential of aldosterone to increase I Ca , using a low Ca 2þ buffering internal solutionthis allows recording Ca 2þ transients as well. Adult rat cardiomyocytes were chronically incubated with 1 mM aldosterone. Subsequently, I Ca and Ca 2þ transients were recorded under whole-cell patch clamp. CM-H 2 CDFDA was used to monitor ROS. Under the present conditions, aldosterone did not alter the peak amplitude of I Ca . However, it promoted 478-PosQuantitative In Silico