Insulin-like 6 Is Induced by Muscle Injury and Functions as a Regenerative Factor

Abstract

The insulin-like family of factors are involved in the regulation of a variety of physiological processes, but the function of the family member termed insulin-like 6 (Insl6) in skeletal muscle has not been reported. We show that Insl6 is a myokine that is up-regulated in skeletal muscle downstream of Akt signaling and in regenerating muscle in response to cardiotoxin (CTX)-induced injury. In the CTX injury model, myofiber regeneration was improved by the intramuscular or systemic delivery of an adenovirus expressing Insl6. Skeletal muscle-specific Insl6 transgenic mice exhibited normal muscle mass under basal conditions but elevated satellite cell activation and enhanced muscle regeneration in response to CTX injury. The Insl6-mediated regenerative response was associated with reductions in muscle cell apoptosis and reduced serum levels of creatine kinase M. Overexpression of Insl6 stimulated proliferation and reduced apoptosis in cultured myogenic cells. Conversely, knockdown of Insl6 reduced proliferation and increased apoptosis. These data indicate that Insl6 is an injury-regulated myokine that functions as a myogenic regenerative factor.

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

“…Because of their powerful ability to regenerate in vivo in response to muscle damage and various stimuli, satellite cells represent important targets for the treatment of muscular diseases (7)(8)(9)(10). The recent development of stem cell-based regenerative medicine strategies has brought enormous interest in the discovery of regulatory factors capable of controlling satellite cell functions, such as activation, proliferation, differentiation, and self-renewal (11)(12)(13). Identification of such factors is expected to not only improve our understanding of the regulatory mechanisms that govern satellite cell functions, but also to facilitate the development of stem cell-based therapies for the treatment of muscular dystrophy or other chronic diseases associated with muscle wasting.…”

Myonectin (CTRP15), a Novel Myokine That Links Skeletal Muscle to Systemic Lipid Homeostasis

“…IL-6 (4), FGF-21 (7,8), insulin-like 6 (Insl6) (9), follistatin-like 1 (Fstl-1; also known as TSC-36) (10), leukemia inhibitory factor (LIF) (11), IL-7 (12), IL-15 (13), and musclin (14) are the currently characterized myokines. These myokines act locally in an autocrine/paracrine manner and/or as endocrine factors linking skeletal muscle to regulation of physiological processes in other tissues.…”

Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

“…Part of our rationale for undertaking this study was our prior observations that INSL6 had roles in attenuating skeletal muscle injury 20, 22. The present study demonstrates that genetic INSL6 deficiency results in exacerbated LV systolic dysfunction in the AngII‐infusion and isoproterenol‐treatment models of heart failure in mice.…”

“…INSL6 is predominantly expressed in testis, and homozygous INSL6‐deficient male mice are infertile 19. Previously, we documented the upregulation of INSL6 in the growing skeletal muscle of mice that were genetically modified to express constitutively active protein kinase B in this tissue 20, 21. INSL6 expression is also upregulated in mouse skeletal muscle after cardiotoxin‐induced skeletal muscle injury, and adenovirus‐mediated overexpression of INSL6 facilitates muscle regeneration in this model 20.…”

“…Previously, we documented the upregulation of INSL6 in the growing skeletal muscle of mice that were genetically modified to express constitutively active protein kinase B in this tissue 20, 21. INSL6 expression is also upregulated in mouse skeletal muscle after cardiotoxin‐induced skeletal muscle injury, and adenovirus‐mediated overexpression of INSL6 facilitates muscle regeneration in this model 20. In a model of experimental autoimmune myositis, INSL6‐deficient mice display greater motor function impairment, whereas INSL6 overexpression protects muscle from dysfunction 22…”