Reciprocal Homer1a and Homer2 Isoform Expression Is a Key Mechanism for Muscle Soleus Atrophy in Spaceflown Mice

Abstract

The molecular mechanisms of skeletal muscle atrophy under extended periods of either disuse or microgravity are not yet fully understood. The transition of Homer isoforms may play a key role during neuromuscular junction (NMJ) imbalance/plasticity in space. Here, we investigated the expression pattern of Homer short and long isoforms by gene array, qPCR, biochemistry, and laser confocal microscopy in skeletal muscles from male C57Bl/N6 mice (n = 5) housed for 30 days in space (Bion-flight = BF) compared to muscles from Bion biosatellite on the ground-housed animals (Bion ground = BG) and from standard cage housed animals (Flight control = FC). A comparison study was carried out with muscles of rats subjected to hindlimb unloading (HU). Gene array and qPCR results showed an increase in Homer1a transcripts, the short dominant negative isoform, in soleus (SOL) muscle after 30 days in microgravity, whereas it was only transiently increased after four days of HU. Conversely, Homer2 long-form was downregulated in SOL muscle in both models. Homer immunofluorescence intensity analysis at the NMJ of BF and HU animals showed comparable outcomes in SOL but not in the extensor digitorum longus (EDL) muscle. Reduced Homer crosslinking at the NMJ consequent to increased Homer1a and/or reduced Homer2 may contribute to muscle-type specific atrophy resulting from microgravity and HU disuse suggesting mutual mechanisms.

Opposite Regulation of Homer Signal at the NMJ Postsynaptic Micro Domain between Slow- and Fast-Twitch Muscles in an Experimentally Induced Autoimmune Myasthenia Gravis (EAMG) Mouse Model

“…In previous studies, we showed that Homer protein family members are conserved in healthy mouse, rat, and human skeletal muscles, and are particularly localised at the postsynaptic microdomain, where they play a key role in coordinating the neuromuscular signal transduction machinery in a mechanism dependent on nerve and muscle activity [ 2 , 9 ]. We therefore set out to study the expression pattern of Homer genes and postsynaptic subcellular localisation in MG-affected skeletal muscles to find out whether they are linked to a proper expression and function of the nicotinic acetylcholine receptor (nAChR) in disease-affected peripheral synapsis.…”

“…In previous studies, we showed that Homer protein family members are conserved in healthy mouse, rat, and human skeletal muscles, and are particularly localised at the postsynaptic microdomain, where they play a key role in coordinating the neuromuscular signal transduction machinery in a mechanism dependent on nerve and muscle activity [2,9].…”

“…Homer proteins are present in mouse, rat, and human skeletal muscles and regulated by nerve and muscle activity [ 2 , 8 ]. For instance, Homer gene transcription, protein expression and subcellular localisation at the NMJ postsynaptic microdomain were downregulated in all human and animal models of disuse-induced muscle atrophy [ 2 , 9 , 10 ]. Moreover, reciprocal expression of Homer 1a and Homer 2 isoform is proposed as a key mechanism responsible for soleus muscle atrophy during chronic exposure to microgravity in space-flown mice [ 9 ].…”

Cellular and Molecular Signaling Meet the Space Environment

“…Furthermore, Blottner et al [ 6 ] conducted a study to investigate the expression pattern of Homer short and long isoforms in the skeletal muscles of male C57Bl/N6 mice after 30 days in space compared to ground-housed animals and rats subjected to hindlimb unloading. The results showed an increase in Homer1a transcripts and the downregulation of Homer2 long-form in the soleus muscle of animals exposed to microgravity or hindlimb unloading, suggesting the possible role of Homer isoforms in neuromuscular junction imbalance/plasticity.…”