The dynamic remodeling of skeletal muscle in size and fiber type composition is a critical adaptive response to meet different functional demands. However, this neural activity-dependent process also contributes to devastating disease states, such as muscle atrophy associated with neuromuscular dysfunction. Elucidating the molecular pathway that connects neural activity to muscle remodeling machinery would not only provide insight into this dynamically regulated physiological process but also offer opportunities for the development of effective therapy for muscle disease such as atrophy. Toward this goal, we have identified HDAC4, a negative regulator of MEF2 transcription factors, as a potential protein critical for neuromuscular activity-dependent muscle atrophy and remodeling. We found that HDAC4 is dramatically and invariably induced and activated in response to denervation and neuromuscular disease-induced atrophy. We have also found that HDAC4 is dynamically associated with the neuromuscular junction (NMJ) where it co-localizes with calcium/calmodulin dependent kinases (CaMK) and 14-3-3, two signaling effectors of neuromuscular activity that were previously shown to regulate HDAC4 function and subcellular localization. Interestingly, upon denervation, HDAC4 dissociates from the NMJ and becomes concentrated to the nucleus in muscle fibers. We showed that HDAC4 can repress the expression of contractile, structural and metabolic proteins implicated in muscle atrophy and remodeling. We propose that HDAC4 is a critical mediator that controls neuromuscular activity-dependent transcriptional reprogramming associated with muscle atrophy and fiber type specification.
Aim 1. To characterize the mechanism by which neural activity regulates HDAC4 expression and activity. We will elucidate the mechanism by which HDAC4 is induced transcriptionally and characterize the regulation of CaMK-dependent HDAC4 phosphorylation and intracellular trafficking in response to neuromuscular dysfunction.
Aim 2. To elucidate the function of HDAC4 in muscle remodeling, atrophy and fiber type transition in response to neuromuscular inactivity. We propose to use genetic mutation, gene transfer and pharmacological HDAC inhibitor to characterize the role of HDAC4 in the execution of muscle atrophy and fiber type transition in response to reduced neuromuscular activity. The proposed study will provide a critical and novel understanding of the signaling events that link neuromuscular activity to muscle remodeling as well as pathological atrophy and metabolic disorders. Given that HDAC4 activity can be inhibited pharmacologically, the proposed study could potentially be translated into a novel clinical treatment for muscle atrophy or muscle disorders associated with neuromuscular dysfunction.
Muscle function and property are controlled by neural input. Neural inactivity caused by neuromuscular disease and aging can lead to muscle atrophy and myofiber transition that contributes to insulin resistance. Elucidating the machinery and signaling pathway that connects neural activity to the reprogramming of muscle phenotype would therefore provide novel therapeutic opportunities for treating muscle atrophy and type II diabetes.
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