Muscle-derived insulin-like growth factor I cannot compensate for global Igf1 deficiency in mice

Insulin-like growth factor I (IGFI) is a central mediator of mammalian growth, yet the relative contributions of systemic versus tissue-restricted IGF-I remain unresolved. We tested whether skeletal muscle-derived IGF-I could support pre- and postnatal growth in the absence of endogenous IGFI. Mice carrying a muscle-specific Igf1 transgene were intercrossed with Igf1 knockout mice and Little mice lacking a functional growth hormone-releasing hormone receptor gene (Ghrhr). Survival, body weight, and circulating IGF-I and growth hormone (GH) concentrations were assessed across genotypes and postnatal ages. Loss of Igf1 resulted in severe perinatal lethality regardless of GH status or transgene presence. In contrast, GH deficiency produced marked growth restriction without comparable lethality when at least one Igf1 allele was present. The presence of the Igf1 transgene (tIGF-I) did not significantly affect circulating IGF-I or GH concentrations or overall body weight. Sex-specific effects of the transgene were observed, consistent with a global background-dependent modulation of IGF-I action. Collectively, these findings demonstrate that endogenous IGF-I is essential for postnatal viability and coordinated somatic growth, whereas skeletal muscle-derived IGF-I appears to function locally, in a non-endocrine manner and does not substitute for loss of normal control of the IGF-I axis.