Glucocorticoids increase skeletal muscle NF-κB inducing kinase (NIK)

Links to muscle atrophy

Christopher Fry, Syed Z. Nayeem, Edgar Dillon, Partha Sarkar, Batbayar Tumurbaatar, Randall Urban, Traver J. Wright, Melinda Sheffield-Moore, Ronald Tilton, Sanjeev Choudhary

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Glucocorticoids (GC) are a frontline therapy for numerous acute and chronic diseases because of their demonstrated efficacy at reducing systemic inflammation. An unintended side effect of GC therapy is the stimulation of skeletal muscle atrophy. Pathophysiological mechanisms responsible for GC-induced skeletal muscle atrophy have been extensively investigated, and the ability to treat patients with GC without unintended muscle atrophy has yet to be realized. We have reported that a single, standard-of-care dose of Methylprednisolone increases in vivo expression of NF-κB-inducing kinase (NIK), an important upstream regulatory kinase controlling NF-κB activation, along with other key muscle catabolic regulators such as Atrogin-1 and MuRF1 that induce skeletal muscle proteolysis. Here, we provide experimental evidence that overexpressing NIK by intramuscular injection of recombinant human NIK via adenoviral vector in mouse tibialis anterior muscle induces a 30% decrease in the average fiber cross-sectional area that is associated with increases in mRNA expression of skeletal muscle atrophy biomarkers MuRF1, Atrogin-1, myostatin and Gadd45. A single injection of GC induced NIK mRNA and protein within 2 h, with the increased NIK localized to nuclear and sarcolemmal locations within muscle fibers. Daily GC injections induced skeletal muscle fore limb weakness as early as 3 days with similar atrophy of muscle fibers as observed with NIK overexpression. NIK overexpression in primary human skeletal muscle myotubes increased skeletal muscle atrophy biomarkers, while NIK knockdown significantly attenuated GC-induced increases in NIK and Atrogin-1. These results suggest that NIK may be a novel, previously unrecognized mediator of GC-induced skeletal muscle atrophy.

Original languageEnglish (US)
Article numbere13014
JournalPhysiological Reports
Volume4
Issue number21
DOIs
StatePublished - Nov 1 2016

Fingerprint

Muscular Atrophy
Glucocorticoids
Skeletal Muscle
Phosphotransferases
Muscles
Biomarkers
Myostatin
Messenger RNA
Injections
Intramuscular Injections
Skeletal Muscle Fibers
Methylprednisolone
Acute Disease
Standard of Care
Protein Kinases
Proteolysis
Chronic Disease
Extremities
Inflammation

Keywords

  • Atrogin-1
  • Catabolism
  • Methylprednisolone
  • MuRF1
  • NF-κB inducing kinase

ASJC Scopus subject areas

  • Physiology (medical)
  • Physiology

Cite this

Glucocorticoids increase skeletal muscle NF-κB inducing kinase (NIK) : Links to muscle atrophy. / Fry, Christopher; Nayeem, Syed Z.; Dillon, Edgar; Sarkar, Partha; Tumurbaatar, Batbayar; Urban, Randall; Wright, Traver J.; Sheffield-Moore, Melinda; Tilton, Ronald; Choudhary, Sanjeev.

In: Physiological Reports, Vol. 4, No. 21, e13014, 01.11.2016.

Research output: Contribution to journalArticle

Fry, C, Nayeem, SZ, Dillon, E, Sarkar, P, Tumurbaatar, B, Urban, R, Wright, TJ, Sheffield-Moore, M, Tilton, R & Choudhary, S 2016, 'Glucocorticoids increase skeletal muscle NF-κB inducing kinase (NIK): Links to muscle atrophy', Physiological Reports, vol. 4, no. 21, e13014. https://doi.org/10.14814/phy2.13014
Fry, Christopher ; Nayeem, Syed Z. ; Dillon, Edgar ; Sarkar, Partha ; Tumurbaatar, Batbayar ; Urban, Randall ; Wright, Traver J. ; Sheffield-Moore, Melinda ; Tilton, Ronald ; Choudhary, Sanjeev. / Glucocorticoids increase skeletal muscle NF-κB inducing kinase (NIK) : Links to muscle atrophy. In: Physiological Reports. 2016 ; Vol. 4, No. 21.
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