Inflammation and muscle wasting - NF-kB signaling and mir-31 regulate muscle function

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Muscle strength and functionality have a severe impact on human quality of life and longevity. Age and chronic diseases cause muscle wasting, and this loss of muscle mass and strength is directly related to negative disease outcomes, disability and mortality rates. Currently no pharmaceutical treatment for muscle loss is available. Other countermeasures such as exercise are less effective in ageing and diseased muscles, as they become more prone to contraction-induced muscle injury causing insufficient recovery. This susceptibility to muscle injury is directly correlated with loss of dystrophin, an essential structural protein that links the cytoskeleton of the muscle fiber to the extracellular matrix. The loss of dystrophin in congenital disorders, but also with age and in non-congenital human diseases is associated with a significant inflammatory and oxidative component. Interventions targeting antioxidative mechanisms were able to partially restore dystrophin. The molecular mechanisms underlying the effects of aging, inflammation and oxidation on dystrophin levels remain poorly understood. Recently, micro RNAs (miRs) that specifically decrease dystrophin translation (dystromirs) have been identified. The Baar laboratory at the University of California has recently shown that one of these miRs (miR-31) is elevated over 6-fold in aging muscle, can directly regulate dystrophin protein levels and is affected by inflammatory signaling through NF-kB. The NF-kB family of transcription factors have been directly tied to muscle wasting due to a multitude of causes, pointing towards a common mechanism. Even though it is clear that NF-kB is important in muscle wasting, its transcriptional targets remain largely unknown. Strong preliminary data indicate that miR-31 levels are increased through a specific inflammatory pathway of canonical NF-kB signaling, but can be decreased through atypical NF-kB signaling protecting muscle from contraction-induced injury.These preliminary data provide a strong rationale for more in depth analysis of the role of the canonical and atypical NF-kB signaling in the regulation of miR-31 and dystrophin levels in old muscles. To understand the interplay between inflammation, mIR-31, dystrophin, and muscle function, we will examine how the balance between canonical/atypical NF-kB signaling regulates miR-31 levels, dystrophin protein, muscle strength and contraction-induced injury. This project is a significant step towards direct mechanistic evidence of the relationship between inflammation, oxidative stress and dystrophin loss. We will investigate interventions to enhance muscle force transfer, decrease contraction-induced muscle injury, and prevent muscle wasting. By furthering our understanding of the molecular mechanisms underlying the loss of dystrophin and the subsequent design of appropriate interventions, we aim to improve the quality of life of millions of patients suffering from muscle loss.