Prolonged disuse of skeletal muscle results in
atrophy, and once physical activity is resumed, there is increased susceptibility to injury.
Insulin-like growth factor-I (
IGF-I) is considered a potential therapeutic target to attenuate
atrophy during unloading and to enhance rehabilitation upon reloading of skeletal muscles, due to its multipronged actions on satellite cell proliferation, differentiation, and survival, as well as its actions on muscle fibers to boost
protein synthesis and inhibit protein degradation. However, the form of
IGF-I delivered may alter the success of treatment. Using the hindlimb suspension model of
disuse atrophy, we compared the efficacy of two
IGF-I forms in protection against
atrophy and enhancement of recovery: mature
IGF-I (IGF-IS) lacking the COOH-terminal extension, called the E-
peptide, and IGF-IA, which is the predominant form retaining the E-
peptide. Self-complementary adeno-associated virus harboring the murine Igf1
cDNA constructs were delivered to hindlimbs of adult female C57BL6 mice 3 days prior to hindlimb suspension. Hindlimb muscles were unloaded for 7 days and then reloaded for 3, 7, and 14 days. Loss of muscle mass following
suspension was not prevented by either
IGF-I construct. However, IGF-IS expression maintained soleus muscle force production. Further, IGF-IS treatment caused rapid recovery of muscle fiber morphology during reloading and maintained muscle strength. Analysis of gene expression revealed that IGF-IS expression accelerated the downregulation of
atrophy-related genes compared with untreated or IGF-IA-treated samples. We conclude that mature-
IGF-I may be a better option than pro-IGF-IA to promote skeletal muscle recovery following
disuse atrophy.