**4. Impairment of the IGF-1 pathway in muscle catabolism**

Endogenous insulin-like growth factor-1 (IGF-1) is a very potent anabolic agent in the human body. IGF-1 is released from the liver after growth hormone (GH) stimulation of liver cells. Another form of IGF-1 (a splice variant) mechanogrowth factor (MGF) is produced by the mechanical loading of skeletal muscle [16] and is released in a paracrine/autocrine fashion and is also a potent anabolic agent. Lambert et al. [14] reported that the combination of chronic aerobic and resistance exercise training in humans, resulted in an upregulation in MGF mRNA in skeletal muscle.

The mechanism of action of IGF-1 in causing muscle protein synthesis is through PI3K/AKT/mTOR signaling [17]. This would also be the pathway via a common receptor by which insulin stimulates muscle protein synthesis. Interestingly, lack of basal IGF-1 signaling resulted in activation of atrogin-1 and Murf-1, two factors that induce muscle protein breakdown through the ubiquitin-proteasome pathway [17, 18]. Additionally, these authors [18] reported when basal IGF-1 levels were absent there was an activation of GSK-3B which phosphorylates and inactivates 4EBP1-a translation (protein synthesis) initiation factor. This activation of muscle protein breakdown through these two mediators resulted in myosin heavy chain 1 and 3 degradation in an animal model. In addition to causing muscle protein synthesis, IGF-1 acts to reduce muscle protein breakdown through reducing atrogin-1 and Murf-1.

In a thorough study on the effects of cancer cachexia on the IGF-1 system in skeletal muscle and plasma, Costelli et al. [19] reported that there was about a 50% reduction in muscle IGF-1 and plasma levels were also reduced. The model they used for cancer cachexia was the Yoshida AH-130 hepatoma model [19].

To summarize, IGF-1 is a potent stimulator of anabolism or muscle growth and impairing the signaling of IGF-1 results in reduced muscle protein synthesis through the PI3K/AKT/mTOR pathway as well as increased muscle protein degradation through an increase in atrogin-1 and Murf-1. Additionally, GSK-3B is activated which inhibits translation initiation by phosphorylating 4EBP-1 when IGF-1 signaling is impaired.
