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Can a Simple Laminin Injection Aid Exercise-Associated Muscle Damage?

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Review of “Laminin-111 Improves Skeletal Muscle Stem Cell Quantity and Function Following Eccentric Exercise” from Stem Cells TM by Stuart P. Atkinson

Many different mechanisms mediate repair of muscle damage after exercise. Muscle stem cells (or satellite cells [SCs]) proliferate and activate and fuse together or to existing myofibers [1], while recent studies have suggested that a non-SC mesenchymal stem cell (MSC)-like cell may also mediate repair through a paracrine action [2]. Additionally, cellular organization and integrity requires the extracellular matrix (ECM) which surrounds each myofiber, and also acts as a niche for SCs [3]. Laminin-111 (LM-111) plays an important role in myoblast proliferation, mobility and myofiber formation [4, 5], and mitigates muscular symptoms associated with muscular dystrophy. With this knowledge in mind, researchers from the group of Marni D. Boppart (Beckman Institute for Advanced Science and Technology, Illinois, USA) have investigated if LM-111 has the potential to promote SC- and MSC-mediated muscle repair after exercise-induced injury in a mouse model [6].

After injection LM-133 localised round individual myofibers and colocalized with Pa7+ SC cells. After one week, mice undertook a single bout of downhill running exercise – so called eccentric exercise which resembles the main cause of injury in human skeletal muscle – and assessed at 24 hours (See Figure). Such exercise itself provokes damage, but a regenerative response is also raised [7]. LM-111 injection led to increased SC quantity, with the highest increase observed following exercise, and induced higher levels of proliferative SCs and newly synthesized myofibers. Further in vitro analysis found that LM-111 had a direct effect on myoblast proliferation. Meanwhile assessment of muscle-associated MSC number found that LM-111 (and/or exercise) did not alter their quantity, but did alter gene expression; evidenced by decreased levels of IL-6, TNFa, IL-1rn and IL-10 (mediate inflammatory responses) and increased levels of HGF (potent activator of satellite cells [8]) in the LM-111 ice who underwent exercise compared to sedentary control mice.

LM-111 seems likely to enhance muscle repair/regeneration after exercise and forms a launch pad for further studies in injured and/or aged muscle, towards its application in human patients where the progressive loss of muscle mass and function with age is a major contributor to decreased quality of life. Further work may also include uncovering further mechanisms by which muscle MSCs stimulate satellite cell expansion in vivo akin to the role of HGF discovered here.

References

  1. Hawke TJ and Garry DJ Myogenic satellite cells: physiology to molecular biology. J Appl Physiol (1985) 2001;91:534-551.
  2. Valero MC, Huntsman HD, Liu J, et al. Eccentric exercise facilitates mesenchymal stem cell appearance in skeletal muscle. PLoS One 2012;7:e29760.3. Merritt EK, Hammers DW, Tierney M, et al. Functional assessment of skeletal muscle regeneration utilizing homologous extracellular matrix as scaffolding. Tissue Eng Part A 2010;16:1395-1405.
  3. Goudenege S, Lamarre Y, Dumont N, et al. Laminin-111: a potential therapeutic agent for Duchenne muscular dystrophy. Mol Ther 2010;18:2155-2163.
  4. Silva-Barbosa SD, Butler-Browne GS, de Mello W, et al. Human myoblast engraftment is improved in laminin-enriched microenvironment. Transplantation 2008;85:566-575.
  5. Zou K, De Lisio M, Huntsman HD, et al. Laminin-111 Improves Skeletal Muscle Stem Cell Quantity and Function Following Eccentric Exercise. Stem Cells Transl Med 2014;
  6. Lueders TN, Zou K, Huntsman HD, et al. The alpha7beta1-integrin accelerates fiber hypertrophy and myogenesis following a single bout of eccentric exercise. Am J Physiol Cell Physiol 2011;301:C938-946.
  7. Miller KJ, Thaloor D, Matteson S, et al. Hepatocyte growth factor affects satellite cell activation and differentiation in regenerating skeletal muscle. Am J Physiol Cell Physiol 2000;278:C174-181.