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Reversing Muscle Stem Cell Aging with pro-IGF-II?

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Review of “Pro-Insulin-Like Growth Factor-II Ameliorates Age-Related Inefficient Regenerative Response by Orchestrating Self-Reinforcement Mechanism of Muscle Regeneration” from Stem Cells by Stuart P. Atkinson.

The loss of skeletal mass and strength with age, known as sarcopenia [1], is a common ailment in the elderly leading to weakness, frailty, and the loss of independence. The stimulation of muscle stem cells may represent a means to reverse this condition and regenerate muscle, although this still remains an unproven therapeutic option with many unresolved factors. These factors include the regenerative capacity of aged skeletal muscle, whether the number of satellite cells actually changes with age, and whether cell-extrinsic factors (microenvironmental factors) are more important than cell-intrinsic factors. 

In a new study in Stem Cells, researchers from the laboratory of Naohiro Hashimoto (National Center for Geriatrics and Gerontology, Ōbu, Japan) aimed to tease apart these contributing elements and discover how they could boost muscle regeneration in the elderly. Their studies find that age-related extrinsic factors contribute to inefficient muscle regeneration and that pro- insulin-like growth factor-II (pro-IGF-II) may be an effective means to reverse age-related deficits in muscle stem cells [2].

Initial assessments found a reduction in the regenerative response following muscle injury in old mice (24-30 month) as compared to young mice (2-3 months), and this correlated strongly to a decrease in the number of muscle stem cells with increased age. However, the stem cells remaining in older mice still maintained myogenic capacity similar to stem cells from young mice, although young muscle stem cells lost their regenerative capacity after transplantation into old muscles. This suggested to the authors that that the loss of muscle regenerative capacity corresponds to an age-dependent change in the cell microenvironment. 

Assessment of environmental factors via cytokine antibody array analysis found that the IGF axis may be important: IGF-II decreased, and two IGF-binding proteins (IGFBP-2 and IGFBP-3) increased in regenerating muscle of aged mice, while muscle regeneration in young mice corresponded to IGF-II induction. However, instead of an induction in the mature form of IGF-II, the authors found an increase in post-translationally processed isoforms (pro-IGF-II and big-IGF-II). Older mice also exhibited a delayed IGF-II response after injury, expressing a lower level of total IGF-II (pro- and big-IGF-II).

Encouragingly, continuous administration of recombinant pro-IGF-II to older mice with muscle injuries inhibited muscle deterioration compared to a mock-injected control, promoted the formation of new myofibers, and reduced the amount of harmful muscle fibrosis. Mechanistically, the study demonstrated that the beneficial effects of pro-IGF-II came from a heightened level of angiogenesis (See Figure A) and the increased proliferation of muscle stem cells (See Figure C).

Overall, the authors have demonstrated that pro-IGF-II may provide the means to reverse muscle stem cells ageing, and, therefore, may represent an interesting therapeutic approach for the treatment of sarcopenia in elderly human patients. The authors propose that the specific effects of pro-IGF-II and not mature IGF-II may be due to differences in bioavailability mediated by IGF binding proteins and IGF-scavenging receptors, which normally reduce IGF-II levels and, therefore, inhibit a pro-regenerative role in this case.

References

  1. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010;39:412-423.
  2. Ikemoto-Uezumi M, Uezumi A, Tsuchida K, et al. Pro-Insulin-Like Growth Factor-II Ameliorates Age-Related Inefficient Regenerative Response by Orchestrating Self-Reinforcement Mechanism of Muscle Regeneration. Stem Cells 2015;33:2456-2468.