Abstract
Regulators of G Protein Signaling (RGS proteins) inhibit G protein-coupled receptor (GPCR) signaling by accelerating the GTP hydrolysis rate of activated Gα subunits. Some RGS proteins exert additional signal modulatory functions, and RGS12 is one such protein, with five additional, functional domains: a PDZ domain, a phosphotyrosine-binding domain, two Ras-binding domains, and a Gα·GDP-binding GoLoco motif. RGS12 expression is temporospatially regulated in developing mouse embryos, with notable expression in somites and developing skeletal muscle. We therefore examined whether RGS12 is involved in the skeletal muscle myogenic program. In the adult mouse, RGS12 is expressed in the tibialis anterior (TA) muscle, and its expression is increased early after cardiotoxin-induced injury, suggesting a role in muscle regeneration. Consistent with a potential role in coordinating myogenic signals, RGS12 is also expressed in primary myoblasts; as these cells undergo differentiation and fusion into myotubes, RGS12 protein abundance is reduced. Myoblasts isolated from mice lacking Rgs12 expression have an impaired ability to differentiate into myotubes ex vivo, suggesting that RGS12 may play a role as a modulator/switch for differentiation. We also assessed the muscle regenerative capacity of mice conditionally deficient in skeletal muscle Rgs12 expression (via Pax7-driven Cre recombinase expression), following cardiotoxin-induced damage to the TA muscle. Eight days post-damage, mice lacking RGS12 in skeletal muscle had attenuated repair of muscle fibers. However, when mice lacking skeletal muscle expression of Rgs12 were cross-bred with mdx mice (a model of human Duchenne muscular dystrophy), no increase in muscle degeneration was observed over time. These data support the hypothesis that RGS12 plays a role in coordinating signals during the myogenic program in select circumstances, but loss of the protein may be compensated for within model syndromes of prolonged bouts of muscle damage and repair.
Highlights
Regulators of G protein Signaling (RGS proteins) are intracellular GTPase-accelerating proteins (GAPs) that attenuate the G protein-dependent signals that cells receive from their external environment [1, 2]
Confirming our prior findings of skeletal muscle expression of RGS12 beginning at embryonic day 9.5 during mouse development [10], more recent data [44] from whole transcriptome shotgun sequencing (RNA-Seq) of mouse gastrocnemius muscle-derived RNA from various developmental stages indicate that Rgs12 is expressed in developing skeletal muscle during fetal and early postnatal time points, and this expression fades over time in mature adult skeletal muscle (Fig 1A; Gene Expression Omnibus GSE108402)
In microarray-based expression studies, Rgs12 is observed to be expressed in Pax7-positive satellite cells from embryonic day E17.5 mice [45]; while still detectable in adult mice, Rgs12 expression decreases over time in the Pax7-positive satellite cell population (Fig 1B), coinciding with the typical timing of satellite cells moving to a quiescent state [46]
Summary
Regulators of G protein Signaling (RGS proteins) are intracellular GTPase-accelerating proteins (GAPs) that attenuate the G protein-dependent signals that cells receive from their external environment [1, 2]. It was previously reported that skeletal muscles of developing mouse embryos express RGS12 [10], suggesting a potential role for this unique RGS family member in the skeletal muscle developmental process; little has since been reported regarding potential function(s) of RGS12 in the signaling pathways underlying the myogenesis program active during both development and muscle repair With regards to the latter, adult skeletal muscle has a remarkable regenerative capacity, largely made possible by a specialized population of stem cells—satellite cells—found in a characteristic niche between the sarcolemma and basal lamina of myofibers [11,12,13]. Some activated satellite cells remain in their niche and return to quiescence as a reservoir, other daughter cells migrate along the sarcolemma differentiate and fuse with either damaged fibers or with other myoblasts to form repaired or de novo myofibers, respectively This process is characterized by PAX7 down-regulation and up-regulation of muscle-specific genes (e.g., MRF4, myogenin) [15]
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