The Role of the IGF-1 Signaling Cascade in Muscle Protein Synthesis and Anabolic Resistance in Aging Skeletal Muscle

Abstract

Sarcopenia is defined as the combined loss of skeletal muscle strength, function, and/or mass with aging. This degenerative loss of muscle mass is associated with poor quality of life and early mortality humans. The loss of muscle mass occurs due to acute changes in daily muscle net protein balance (NPB). It is generally believed a poor NPB occurs due to reduced muscle protein synthetic responses to exercise, dietary amino acid availability, or an insensitivity of insulin to suppress breakdown. Hence, aging muscles appear to be resistant to the anabolic action of exercise and protein (amino acids or hormonal) when compared to their younger counterparts. The mechanisms that underpin anabolic resistance to anabolic stimuli (protein and resistance exercise) are multifactorial and may be partly driven by poor lifestyle choices (increased sedentary time and reduced dietary protein intake) as well as an inherent dysregulated mechanism in old muscles irrespective of the environmental stimuli. The insulin like growth factor 1 (IGF-1), Akt /Protein Kinase B and mechanistic target of rapamycin (mTOR) pathway is the primary driver between mechanical contraction and protein synthesis and may be a site of dysregulation between old and younger people. Therefore, our review aims to describe and summarize the differences seen in older muscle in this pathway in response to resistance exercise (RE) and describe approaches that researchers have sought out to maximize the response in muscle. Furthermore, this review will present the hypothesis that inositol hexakisphosphate kinase 1 (IP6K1) may be implicated in IGF-1 signaling and thus sarcopenia, based on recent evidence that IGF-1 and insulin share some intracellular bound signaling events and that IP6K1 has been implicated in skeletal muscle insulin resistance.

Keywords: Akt; IP6K1; aging; anabolic resistance; mTOR; protein; resistance exercise; sarcopenia.

Figure 1

The response of muscle protein synthesis (MPS) and breakdown (MPB) on net protein balance after acute resistance exercise or protein ingestion in young and aging populations [Adapted from Breen and Phillips (12)]. In the morning after an overnight fast, muscle protein breakdown exceeds muscle protein synthesis such that net protein balance is negative. After a bout of resistance exercise or the ingestion of protein, young people respond greater in their myofibrillar protein synthesis response compared to aging people, which is appears to be the major attenuating factor to decreased NPB leading to skeletal muscle protein loss over time. MPS, Muscle protein synthesis; MPB, Muscle protein breakdown.

Figure 2

Normal fluctuations in Muscle Protein Synthesis and Muscle Protein Breakdown rates throughout the day in response to eating a protein containing meal and the effect this has on net protein balance. Protein Requirements to stimulate myofibrillar protein synthesis rates in young and aging populations are described in g/kg of lean body mass These protein meal requirements should be spread equally throughout the day (i.e., 4–5 meal times) to facilitate non-hypertrophic protein remodeling and counterbalance fasting-state protein losses that occurred in between meals (81). MPS, Muscle protein synthesis; MPB, Muscle protein breakdown; LBM, Lean body mass.

Figure 3

Schematic diagram illustrating the potential negative role of IP6K1 on Akt translocation to the cell membrane preventing phosphorylation of Akt³⁰⁸ which may reduce mTORC1. IP6K1 enters the nucleus via PA and it then synthesizes IP7 from IP6 which prevents Akt from translocating to the cell membrane and ultimately preventing Akt³⁰⁸ phosphorylation. IGFBP, Insulin like growth factor binding proteins; IGF-1, Insulin like growth factor-1; IP6K1, inositol hexakisphosphate kinase 1; IGFR, Insulin like growth factor receptor; IRS-1, Insulin receptor substrate 1; P13K, phosphoinositide 3-kinase; PIP2, hosphatidylinositol (4, 5)-bisphosphate; PIP3, hosphatidylinositol 3,4,5-trisphosphate; PDK1, phosphoinositide-dependent kinase-1; Akt, Protein kinase B; mTORC2, Mechanistic target of rapamycin; PA, Phosphotadic acid; IP6, inositol hexaphosphate; IP7, Inositol pyrophosphate; Illustrates contraction of skeletal muscle; Illustrates binding/translocationto the cell membrane; Illustrates activation; Illustrates phosphorylation; Illustrates binding to PH domain and downregulating Akt; Illustrates preventing translocation to cell membrane.