Molecular Cascades of Resistance Training induced Skeletal Muscle Hypertrophy: A Molecular Physiological perspective.

In this article I discuss of a relatively new topic,The Cellular and Molecular Cascades of Skeletal Muscle Hypertrophy. It is perhaps a hot area for research in Molecular Exercise Physiology and Exercise genetics in vogue. Exercise Physiologist and Exercise practitioners may be very familiar with the Physiological Mechanism of Skeletal muscle hypertrophy.Muscle hypertrophy can be considered distinct and separate from muscle hyperplasia. During hypertrophy contractile elements enlarge and the extracellular matrix expands to support growth (Vierck J et all 2000). However muscle volumaization depends on both hypertrophy and hyperplasia. This article will provide a research based understanding of biomolecular cross talks and cascades that regulate resistance training induced muscle growth.This article's prime focus is on IGF-1(Insulin Like Growth Factor-1) mediated skeletal muscle hypertrophy through the activation of sarcoplasmic (cellular) signaling pathway PI3k/Akt/mTOR ( Mammalian Target of Rapamycin).
 A profound understanding of molecular and genetic factors that mediate skeletal muscle hypertrophy and the impact of mechanical loading on such molecular processes will enable Nutritionists,exercise physiologists & practitioners to develop new and more effective supplements and training protocols for athletes to prevent Over Training Syndrome and recover from OTS. It will also be helpful for rehabilitation specialists,clinical exercise physiologist & HFS's to develop systematic therapeutic resistance training programs for the management and prevention of  Cancer Cachexia , HIV induced Cachexia , other diseases and againg induced muscle wasting.         

For a conceptual understanding of the topic, I will briefly discuss What IGF-1 is ? and What PI3k/Akt/mTOR pathway is ? accompanied by brief reviews of current research on the role of mechanical loading of skeletal muscle on the IGF-1 mediated PI3k/Akt/mTOR pathway activation & skeletal muscle Hypertrophy.

IGF-1

Insulin Like Growth Factor-1 or Somatomedian C is a protein that in human is encoded by IGF-1 gene.( Jansen.M et All 1983). It is a cellular signaling molecule which  has a molecular structure similar to that of insulin. In human it is chiefly secreted by liver and skeletal muscle tissue. It acts like growth hormone in both autocrine and paracrine manner on skeletal muscle tissue by binding to IGF-1r. It plays an important  anabolic role in adult skeletal muscle  growth. IGF-1 isforms  have  significant role in cellular processes of many tissue types. IGF-1r's are mainly expressed in satellite cell population. Satellite cells are the mononuclear progenitor cells of skeletal muscles.For several years research have focused on IGF-1 mediated skeleltal muscle growth in response to resistance exercise.Many studies have found exercise induces IGF-secretion.IGF-1 isoforms binds to specific receptors in muscles cell surface and activates growth stimulating pathway( PI3k/Akt/mTOR Path way).To date several isoforms of IGF-1 have been found in human and other animals. 
Of which IGF-1c isoform has been observed to be increasingly expressed at the onset of satellite cell proliferation in response to muscle cell damage induced by muscle lengthening contractions in human(McKay BR et all 2008).
IGF1/PI3k/Akt/mTORcomplex is a potent stimulator of sarcoplasmic growth.IGF1/PI3k/Akt/mTOR complex stimulates skeletal muscle hypertrophy by inhibiting the effect of a protein called Myostatin ( a member of TGF-beta family). Deletion or inhibition of Myostatin causes an increase in skeletal muscle size because myostatin acts both to inhibit the myoblast differentiation and to block the Akt pathway( David J Glass 2011). 

PI3k/Akt/mTOR pathway

It is an intracellular signaling pathway contributes to  Muscle Hypertrophy. It is activated by IGF-1 and has a number of downstream effects which either promote protein synthesis( proteogenesis) or prevent protein breakdown ( proteolysis). The IGF-1 mediated downstream signaling cascades of PI3k/Akt/mTOR pathway is complex and will be difficult for those with little back-ground in molecular physiology to understand. Therefore, I will try to present in a simple and comprehensible manner for Exercise Physiologist and exercise professionals in general. IGF-1 acts in a hormone like manner by binding to IGF-1r in skeletal muscle tissue, especially in satellite cells. Ligand binded IGF-1r activates intracellular signaling transducer enzyme PI3k ( phospho ionosetide 3 kinase) this in turn lead to the activation of Akt or PKB( Protein Kinase B).It is an enzyme that  plays key role in glucose metabolism, cell proliferation, transcription and cell migration. IGF-1/PI3k/Akt complex binds to mTOR or Mammalian Target of Rapamycin. Specifically to mTOR isoform Mammalian Target Of Rapamycin Complex-1. It is a protein that in human is encoded by MTOR gene.It act as a catalyst of Cell growth, proliferation, Cell motility , cell survival, protein synthesis and transcription.
 IGF-1's pro-hypertrophy activity comes predominantly through its ability to activate PI3k/Akt signaling pathway ( Glass DJ 2010). The IGF1/PI3k/Akt/mTOR pathway, which has been shown to induce, hypertrophy, prevent induction of requisite atrophy mediators namely the Muscle Specific Ubiquitin Ligases (MAFBx) and Muscle RING-finger protein1( MuRF1)(Trevor.M.Stitt et All 2004). Akt phosphoryates and inactivates Tuberosclerosis Complex 2 ( TSC2) resulting in the activation of mTOR. mTOR phosphorylates 70KDa ribosomal S6 protein kinase (p70S6K1) resulting in an increase in muscle protein synthesis( Peter Tiidus, A Russel Tupling,Michael Houston 2012). The Mammalian Target of Rapamycin complex 1(mTORC1) pathway is the primary regulator of skeletal muscle growth. Bodine et all in 2001 reported that the over expression of Akt in mice resulted in an astonishing amount of skeletal muscle hypertrophy mediated by the activation of mTORC1 signaling pathway.2011 Miyazaki et all demonstrated IGF-1/PI3k/Akt non-depended activation of mTORC1 and skeletal muscle hypertrophy in C57BL/6J mice.However so far no studies in human have reported supportive evidence for IGF-1/PI3k/Akt non- depended activation of mTORC1 pathway( mTOR).  
       

IGF-1/PI3k/Akt/mTOR Pathway 

     

                             

  

     Siby C Chacko BPE,MPE ( Exercise Physiology)

References

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    Following miotruma caused by resistance exercise. Cell.Bio.Int. 24: 263-272 (2000)

2) Jansen.M, Van Schaic FM,Ricker AT,Bulock.B, Woods.DE, Gabby K H and Nussbum AL , Sequence of cDNA Human Insulin Like Growth factor - 1 precursor.Nature: 306(5943) 609-11.(1983).

3) David J Glass , PI3 kinase regulation of skeletal muscle hypertrophy and atrophy. curr.top.in.micro bio
   and immuno Vol. 346 pp 267-278(2010)

4) Mc Kay BR,O'Reilly,Philips SM, Tarnopolsky MA and Parise.G, Co- expression of IGF
    Family members with Myogenic regulatory factors with folowing acute damaging muscle  
    lengthening contractions in Human. J.Physio.586: 5549-5560 (2008).

5)  David J Glass , PI3 kinase regulation of skeletal muscle hypertrophy and atrophy. curr.top.in.micro bio
   and immuno Vol. 346 pp 267-278(2010). 

6) Trevor.N.Stitt, Doreen Drujan, Brian A Clark, Frank Panaro,David J Glass et all.
     The IGF-1?PI3k/Akt pathway Prevents expression of Muscle Atrophy induced Ubiquitin Ligases
      by inhibiting FOXO Transcription factors. Mollecular Cell Vol.14(3)pp-395-403 (2004).

7) Peter Tiidus, A Russel Tupling,Michael , Houston , Biochemistry Primer for exercise Science 4th edition
     chap-3 pp:39-70 (2012).

8) Bodine SC , Stitt.T.N, Gonzalez.M,Kline W.O,Glass DJ et all . Akt/mTOR pathway is a crucial 
    regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat.cell.bio 3(11)1014-1019(2001).