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Skelet Muscle. 2014 Aug 4;4:16. doi: 10.1186/2044-5040-4-16. eCollection 2014.

The injury-induced myokine insulin-like 6 is protective in experimental autoimmune myositis.

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Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, W611, Boston, MA 02118, USA.
Institute of Human Genetics, University of Göttingen, Göttingen, Germany.
Hematology Oncology Section, Boston University School of Medicine, 715 Albany Street, W611, Boston, MA 02118, USA.
Department of Neurology, Rhode Island Hospital, Brown University School of Medicine, 593 Eddy St, Providence, RI 02903, USA.



The idiopathic inflammatory myopathies represent a group of autoimmune diseases that are characterized by lymphocyte infiltration of muscle and muscle weakness. Insulin-like 6 (Insl6) is a poorly characterized member of the insulin-like/relaxin family of secreted proteins, whose expression is upregulated upon acute muscle injury.


In this study, we employed Insl6 gain or loss of function mice to investigate the role of Insl6 in a T cell-mediated model of experimental autoimmune myositis (EAM). EAM models in rodents have involved immunization with human myosin-binding protein C with complete Freund's adjuvant (CFA) emulsions and pertussis toxin.


Insl6-deficiency in mice led to a worsened myositis phenotype including increased infiltration of CD4 and CD8 T cells and the elevated expression of inflammatory cytokines. Insl6-deficient mice show significant motor function impairment when tested with treadmill or Rotarod devices. Conversely, muscle-specific overexpression of Insl6 protected against the development of myositis as indicated by reduced lymphocyte infiltration in muscle, diminished inflammatory cytokine expression and improved motor function. The improvement in myositis by Insl6 could also be demonstrated by acute hydrodynamic delivery of a plasmid encoding murine Insl6. In cultured cells, Insl6 inhibits Jurkat cell proliferation and activation in response to phytohemagglutinin/phorbol 12-myristate 13-acetate stimulation. Insl6 transcript expression in muscle was reduced in a cohort of dermatomyositis and polymyositis patients.


These data suggest that Insl6 may have utility for the treatment of myositis, a condition for which few treatment options exist.


Autoimmune; Insulin-like 6; Myokine; Myositis; Skeletal muscle; T cells

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