Targeting Myofiber NAD(P)H Oxidases in Sepsis-Induced Myopathy

University Of Florida, Gainesville FL

Investigators

Abstract

Sepsis is a life-threatening polymicrobial infection that affects approximately 49 million individuals worldwide each year and accounts for nearly 20% of global mortality. Among survivors, up to 75% develop a persistent myopathy characterized by muscle wasting, weakness, and impaired regenerative capacity, for which no effective therapies currently exist. Prolonged immobilization during critical illness further exacerbates muscle loss and contributes to long-term frailty. Despite its clinical relevance, the mechanistic interplay between sepsis, disuse, and redox-dependent muscle dysfunction remains poorly defined, limiting the development of targeted interventions. Excessive production of reactive oxygen species (ROS) is a hallmark of sepsis-induced muscle pathology. NADPH oxidases (NOX) are major enzymatic sources of ROS in skeletal muscle, with NOX2 and NOX4 being the predominant isoforms upregulated during sepsis. Our preliminary data demonstrate that NOX activation drives oxidative stress, myofiber atrophy, and contractile dysfunction, and that combined inhibition of NOX2 and NOX4 preserves muscle strength and protein synthesis in septic mice. These findings implicate NOX-derived ROS as a causal mediator of sepsis-induced myopathy. The overall goal of this project is to define the specific contribution of myofiber-derived NOX2 and NOX4 signaling to muscle weakness, wasting, and impaired regeneration during sepsis complicated by disuse. To achieve this, we will use a novel myoAAV-mediated, myofiber-specific deletion strategy that allows efficient and temporally controlled targeting of Nox2 and Nox4 without the need for inducible transgenic breeding. In Aim 1, we will determine whether myofiber-specific deletion of Nox2, Nox4, or both isoforms mitigates sepsis-induced muscle weakness and atrophy during hindlimb disuse by preserving contractile function, promoting protein synthesis, reducing proteolysis and inflammatory infiltration, and normalizing redox-sensitive proteomic signatures. In Aim 2, we will test whether myofiber NOX-derived ROS contribute to satellite cell dysfunction in sepsis by assessing satellite cell abundance, proliferative and myogenic capacity, and transcriptional and epigenetic programs governing regenerative potential. The proposed studies will establish a direct mechanistic link between myofiber-specific NOX signaling, redox imbalance, and impaired muscle regeneration during sepsis and disuse. By integrating a clinically relevant model of sepsis-associated immobilization with cell-type–specific genetic manipulation, this work will identify tractable redox targets for preserving skeletal muscle mass and function in septic patients and advancing therapeutic strategies to improve long-term recovery after critical illness.