P.447 - From voltage sensing to gene expression in the control of muscle mass homeostasis

Abstract

Muscle mass undergo to rapid and significant changes according to environmental and pathological conditions. Among the various trophic signals, intrinsic muscle contractile activity, neurotransmission and neurotrophic factors are crucial components regulating the integrity of muscle mass.Alterations in the pattern of nerve-evoked electrical activity convey in an excitation-transcription (E-T) coupling crucial for isotypic determination of muscle fibers but also for plastic adaptation and compensation after the loss of muscle mass. When electrical activity is impaired, e.g. neuromuscular diseases, disuse or aging, massive muscle atrophy is observed.Disuse atrophies are generally characterized by a later phase in which muscle wasting is stabilized. This observation has suggested that molecular responses counteracting mass lost take place. Few components of these responses have been identified; in particular, a crucial role is played by the GDF5/Smad4 pathway. Nevertheless, it is still unknown which protein acts as first trigger of atrophy/compensation after an electrical activity alteration.Good candidates could be molecules implicated in the muscle voltage sensing, and we focused our study on the intracellular subunit of the L-type calcium channel complex CaV1.1, CaVb1. Recent publications show that CaVb1 can be at the membrane but also in free cytoplasmic or nuclear pool. This property is essential for the role of CaVb1 as transcription factor regulating myogenin in MPCs. Our study shows that a novel splicing isoform of CaVb1 drives the compensatory response against muscle wasting after denervation. We demonstrate that CaVb1 acts as a first modulator of the BMP14/SMAD4 signaling, conferring to the muscle its intrinsic ability to counteract the atrophy due to electrical activity alterations. The elucidation of the role of CaVb1 in pathological (neuromuscular diseases) and physiological (aging) conditions will bring very new knowledge on muscle pathophysiology.