Obestatin treatment links mitochondrial homeostasis and skeletal muscle repair in Duchenne muscle dystrophy

TL;DR

Obestatin treatment improves muscle repair and mitochondrial function in Duchenne muscular dystrophy by activating specific signaling pathways.

Contribution

The study identifies PPP3 as a key node in obestatin signaling for muscle homeostasis and repair in DMD.

Findings

Obestatin activates TFEB and NFATc1 to restore mitochondrial biogenesis and muscle function.

Obestatin reduces muscle damage and improves contractile function in DMD models.

Obestatin promotes utrophin expression via NFATc1, aiding muscle repair.

Abstract

Duchenne muscular dystrophy (DMD) is a genetic, progressive neuromuscular disease caused by mutations in the dystrophin protein which compromise the integrity of the sarcolemma. Current care of DMD involves both supportive and targeted disease modifying medications. Obestatin, a peptide derived from preproghrelin, is a potential candidate to enhance existing treatments for DMD. This study was conducted to analyse the molecular mechanism by which obestatin acts on myofiber metabolism and muscle restructuring in DMD. Through human and animal models of DMD, we identify the calcium-activated protein phosphatase 3 (PPP3) as key node in obestatin signalling for restoration of muscle homeostasis and activation of membrane repair. In particular, we describe how obestatin signalling recovers muscle function by coordinated activation of the transcription factor EB (TFEB) and the nuclear factor of activated T cell (NFATc1) in which PPP3 is a core component. TFEB dephosphorylation triggers its nuclear translocation and the activation of macroautophagic/autophagic and mitochondrial biogenesis. NFATc1 promotes the slow myofiber phenotype fibre marker utrophin. Overall, obestatin treatment ameliorates distinctive dystrophic features of DMD, including muscle contractile damage, elevated serum creatine kinase levels, and reduced muscle force. Hence, obestatin represents a promising therapeutic approach for treating DMD, not only as monotherapy but also as part of combinatorial treatment strategies aimed at overcoming the barriers that limit the efficacy of gene or cell therapy.

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