The therapeutic potential of IGF-I in skeletal muscle repair

Abstract

Skeletal muscle loss due to aging, motor-neuron degeneration, cancer, heart failure, and ischemia is a serious condition for which currently there is no effective treatment. Insulin-like growth factor 1 (IGF-I) plays an important role in muscle maintenance and repair. Preclinical studies have shown that IGF-I is involved in increasing muscle mass and strength, reducing degeneration, inhibiting the prolonged and excessive inflammatory process due to toxin injury, and increasing the proliferation potential of satellite cells. However, clinical trials have not been successful due to ineffective delivery methods. Choosing the appropriate isoforms or peptides and developing targeted delivery techniques can resolve this issue. Here we discuss the latest development in the field with special emphasis on novel therapeutic approaches.

Figure 1. Mechnisms of sarcopenia

Sarcopenia is caused by multiple factors which include the production of IL-6, TNFα as a result of chronic inflammation; reduced blood flow due to blood vessel dysfunction; dennervation; imbalance between TNF and Notch activity; reduced physical activity and loss of appetite.

Figure 2. Compensatory axon sprouting for motor neuron diseases

Muscle atrophy associated with neuromuscular diseases is caused by denervation of muscles resulting from degeneration of the motor neurons. IGF-I treatment can induce muscle hypertrophy, but reinnervation of the muscle fibers is accomplished by axon sprouting from remaining intact normal motor neurons. Collateral sprouting requires CNTF which is expressed in Schwann cells surrounding axons.

Figure 3. Combination therapy

IGF-I plays a central role in muscle repair and regeneration. Specifically, IGF-I plus inhibitors of activin/myostatin receptor ActRIIB, renin–angiotensin–aldosterone system (RAS) and Smad3 may be beneficial for cancer cachexia, cardiac cachexia and sarcopenia, respectively; whereas IGF-I in combination with stimulators of the Notch pathway, VEGF and CNTF may be a good strategy for treatment of sarcopenia, ischemia reperfusion injury (I/R) and motor neuron diseases, respectively.

Figure I. BOX 2: IGF-I isoforms

The IGF-I gene has two promoters and six exons. Adapted from Velloso et al[86] with modifications. Exon 1 or 2 encodes the initial amino acids of a leader peptide. Exon 3 encodes the remaining of the leader peptide and a portion of the mature IGF-I peptide. Exon 4 encodes the remaining part of the mature peptide and the first 16 amino acids of the E peptides. The rest of the E peptide is encoded by exon 5 (Eb), exon 6 (Ea) or an insert from exon 5 (49 bp in humans, 52 bp in rodents) spliced onto exon 6 (Ec). IGF-IEc (IGF-IEb in rodent) is also called mechano growth factor (MGF)