Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models
Open accessAbstract
A highly conserved signaling pathway involving insulin-like growth factor 1 (IGF1), and a cascade of intracellular components that mediate its effects, plays a major role in the regulation of skeletal muscle growth. A central component in this cascade is the kinase Akt, also called protein kinase B (PKB), which controls both protein synthesis, via the kinases mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK3β), and protein degradation, via the transcription factors of the FoxO family. In this paper, we review the composition and function of this pathway in skeletal muscle fibers, focusing on evidence obtained in vivo by transgenic and knockout models and by muscle transient transfection experiments. Although this pathway is essential for muscle growth during development and regeneration, its role in adult muscle response to mechanical load is less clear. A full understanding of the operation of this pathway could help to design molecularly targeted therapeutics aimed at preventing muscle wasting, which occurs in a variety of pathologic contexts and in the course of aging.
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The Akt-mTOR pathway is central to the regulation of muscle mass because it promotes protein synthesis and inhibits protein degradation.
“The Akt‐mTOR pathway is central to the regulation of muscle mass because it promotes protein synthesis and inhibits protein degradation (Schiaffino & Mammucari, 2011).”
From Parkin overexpression protects from ageing‐related loss of muscle mass and strength (2019) · cites this paper as Schiaffino & Mammucari, 2011
Phytoecdysteroids present in cosmetic preparations protect skin from pigmentation and aging.
“Additionally, it has been discovered that PEs present in cosmetic preparation protect skin from pigmentation and aging163.”
From The Phytochemical, Biological, and Medicinal Attributes of Phytoecdysteroids: An Updated Review (2021) · cites this paper as [163]
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“Mice overexpressing FoxO1 under a musclespecific promoter have muscle atrophy and increased levels of the lysosomal protease cathepsin L [ 90 ].”
BackgroundSmad2 and 3 transcription factors control muscle mass in adulthood
Sartori, R., Milan, G., Patron, M., Mammucari, C., Blaauw, B., Abraham, R., & Sandri, M. (2009) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00104.2009 · Cited by 517 · cited 1× · see citing works
“Myostatin, together with activin A, another member of the TGFb family, acts via its receptor activin receptor IIB (ActRIIB) on Smad2 and Smad3, inhibitors of Akt; conversely, mTOR inhibits Smads [17,18].”
BackgroundSelf-citationGangloff, Y.-G., Mueller, M., Dann, S. G., Svoboda, P., Sticker, M., Spetz, J.-F., Um, S. H., Brown, E. J., Cereghini, S., Thomas, G., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.21.9508-9516.2004 · Cited by 485 · cited 1× · see citing works
“TSC2 null Embryonic lethality [127] mTOR null Embryonic lethality [ 128 ,129]”
BackgroundMuscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice
Barton, E. R., Morris, L. D., Musarò, A., Rosenthal, N. A., & Sweeney, H. L. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200108071 · Cited by 450 · cited 1× · see citing works
“Surprisingly, Akt activation was not detected in these mice [52], suggesting that IGF1 may signal via alternative pathways.”
BackgroundConditional Activation of Akt in Adult Skeletal Muscle Induces Rapid Hypertrophy
Lai, K.-M. V., Gonzalez, M., Poueymirou, W. T., Kline, W. O., Na, E., Zlotchenko, E., Stitt, T. N., Economides, A. N., Yancopoulos, G. D., & Glass, D. J. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.21.9295-9304.2004 · Cited by 442 · cited 1× · see citing works
“HSA-Akt1, inducible Viable Muscle hypertrophy [79]”
Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486
Small, E. M., O'Rourke, J. R., Moresi, V., Sutherland, L. B., McAnally, J., Gerard, R. D., Richardson, J. A., & Olson, E. N. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1000300107 · Cited by 411 · cited 1× · see citing works
“A skeletal muscle- and cardiac-enriched microRNA, miR-486, has been shown to target and inhibit the PI3K inhibitor PTEN, thus activating the Akt pathway [ 72 ].”
BackgroundKOBAYASHI, T., DEAK, M., MORRICE, N., & COHEN, P. (1999) · Biochemical Journal · doi:10.1042/bj3440189 · Cited by 405 · cited 1× · see citing works
“A potential alternative pathway could be the serum- and glucocorticoid-responsive kinase 1 (SGK1), a PI3K-dependent kinase with structural homology to Akt, which is strongly expressed in many tissues, including skeletal muscle and heart [53].”
BackgroundPallafacchina, G., Calabria, E., Serrano, A. L., Kalhovde, J. M., & Schiaffino, S. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.142166599 · Cited by 402 · cited 7× · see citing works
“Note the striking hypertrophy of labeled myofibers compared with untransfected neighbouring fibers. Modified from [ 69 ].”
BackgroundInfluentialSelf-citationFast/Glycolytic Muscle Fiber Growth Reduces Fat Mass and Improves Metabolic Parameters in Obese Mice
Izumiya, Y., Hopkins, T., Morris, C., Sato, K., Zeng, L., Viereck, J., Hamilton, J. A., Ouchi, N., LeBrasseur, N. K., & Walsh, K. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.11.003 · Cited by 395 · cited 1× · see citing works
“MCK-myrAkt1, inducible Viable Muscle hypertrophy [80]”
Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1
Tsukiyama–Kohara, K., Poulin, F., Kohara, M., DeMaria, C. T., Cheng, A., Wu, Z., Gingras, A., Katsume, A., Elchebly, M., Spiegelman, B. M., et al. (2001) · Nature Medicine · doi:10.1038/nm1001-1128 · Cited by 392 · cited 1× · see citing works
“4EBP3 is not expressed in muscle [120]”
Ohanna, M., Sobering, A. K., Lapointe, T., Lorenzo, L., Praud, C., Petroulakis, E., Sonenberg, N., Kelly, P. A., Sotiropoulos, A., & Pende, M. (2005) · Nature Cell Biology · doi:10.1038/ncb1231 · Cited by 392 · cited 2× · see citing works
“S6K1 and S6K2 doubleknockout mice have reduced muscle fiber size with unchanged number of myonuclei [ 89 ].”
BackgroundOnda, H., Lueck, A., Marks, P. W., Warren, H. B., & Kwiatkowski, D. J. (1999) · Journal of Clinical Investigation · doi:10.1172/jci7319 · Cited by 391 · cited 1× · see citing works
“TSC1 null Embryonic lethality [126] TSC2 null Embryonic lethality [ 127 ]”
BackgroundDraznin, B. (2006) · Diabetes · doi:10.2337/db06-0391 · Cited by 390 · cited 1× · see citing works
“Activation of IRS types is inhibited by phosphorylation of serine residues induced by inflammatory cytokines such as tumor necrosis factor a (TNFa) via Jun N-terminal kinase (JNK) [15].”
BackgroundProtein Kinase Bα/Akt1 Regulates Placental Development and Fetal Growth
Yang, Z.-Z., Tschopp, O., Hemmings-Mieszczak, M., Feng, J., Brodbeck, D., Perentes, E., & Hemmings, B. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302847200 · Cited by 384 · cited 1× · see citing works
“Akt3 is not expressed in muscle [4,116]”
Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy
Risson, V., Mazelin, L., Roceri, M., Sanchez, H., Moncollin, V., Corneloup, C., Richard-Bulteau, H., Vignaud, A., Baas, D., Defour, A., et al. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200903131 · Cited by 381 · see citing works
Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats
Adams, G. R., & McCue, S. A. (1998) · Journal of Applied Physiology · doi:10.1152/jappl.1998.84.5.1716 · Cited by 377 · see citing works
Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes
Fernández, A. M., Kim, J. K., Yakar, S., Dupont, J., Hernandez-Sanchez, C., Castle, A. L., Filmore, J., Shulman, G. I., & Le Roith, D. (2001) · Genes & Development · doi:10.1101/gad.908001 · Cited by 369 · cited 1× · see citing works
“IGF1 receptor(2) Viable Transient delay of postnatal muscle growth; unaffected overload-induced muscle hypertrophy; impaired muscle regeneration [59-62]”
BackgroundFoxOs Inhibit mTORC1 and Activate Akt by Inducing the Expression of Sestrin3 and Rictor
Chen, C.-C., Jeon, S., Bhaskar, P. T., Nogueira, V., Sundararajan, D., Tonic, I., Park, Y., & Hay, N. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.03.008 · Cited by 369 · cited 1× · see citing works
“FoxO factors have been shown to inhibit mTORC1 and activate Akt by inducing the expression of sestrin3 and Rictor in cultured mammalian cells [12], but this pathway has not been characterized in skeletal muscle in vivo.”
BackgroundBacquer, O. L., Petroulakis, E., Paglialunga, S., Poulin, F., Richard, D., Cianflone, K., & Sonenberg, N. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29528 · Cited by 365 · see citing works
Waddell, D. S., Baehr, L. M., van den Brandt, J., Johnsen, S. A., Reichardt, H. M., Furlow, J. D., & Bodine, S. C. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00646.2007 · Cited by 360 · see citing works
Abnormal Angiogenesis in Foxo1 (Fkhr)-deficient Mice
Furuyama, T., Kitayama, K., Shimoda, Y., Ogawa, M., Sone, K., Yoshida-Araki, K., Hisatsune, H., Nishikawa, S.-I., Nakayama, K., Nakayama, K., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m314214200 · Cited by 341 · cited 1× · see citing works
“4EBP1+4EBP2 null Viable Normal growth [131] FoxO1 null Embryonic lethality [ 132 ,133]”
BackgroundPI3 kinase regulation of skeletal muscle hypertrophy and atrophy.
Glass, D. (2010) · Current Topics in Microbiology and Immunology · doi:10.1007/82_2010_78 · Cited by 330 · cited 1× · see citing works
“Various aspects of the role of this pathway in skeletal muscle have been previously discussed [1-3].”
BackgroundLagirand-Cantaloube, J., Offner, N., Csibi, A., Leibovitch, M.-P., Batonnet‐Pichon, S., Tintignac, L. A. J., Segura, C. T., & Leibovitch, S. A. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.52 · Cited by 328 · cited 1× · see citing works
“MAFbx also appears to control protein synthesis by ubiquitylating and thus promoting the degradation of the eukariotic translation initiation factor 3 subunit F (eIF3F), thus suppressing S6K1 activation by mTOR [10,11].”
BackgroundEssential role of PDK1 in regulating cell size and development in mice
Lawlor, M. A., Mora, A., Ashby, P. R., Williams, M. R., Murray-Tait, V., Malone, L., Prescott, A. R., Lucocq, J. M., & Alessi, D. R. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf387 · Cited by 320 · cited 1× · see citing works
“PTEN null in heart & muscle (MCK-Cre) Viable Cardiac hypertrophy but normal skeletal muscle growth; unaffected overload-induced muscle hypertrophy; improved muscle regeneration [70,71,123] PDK1 null Embryonic lethality [ 124 ]”
BackgroundHornberger, T. A., Chu, W. K., Mak, Y. W., Hsiung, J. W., Huang, S. A., & Chien, S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600678103 · Cited by 312 · cited 1× · see citing works
“mTOR can also be directly activated independently of PI3K/Akt signaling, by phosphatidic acid, generated by phospholipase D (PLD) in response to mechanical signals induced by eccentric muscle contractions [27-29].”
BackgroundFruman, D. A., Mauvais‐Jarvis, F., Pollard, D. A., Yballe, C. M., Brazil, D. P., Bronson, R. T., Kahn, C. R., & Cantley, L. C. (2000) · Nature Genetics · doi:10.1038/81715 · Cited by 287 · see citing works
A Foxo/Notch pathway controls myogenic differentiation and fiber type specification
Kitamura, T., Kitamura, Y. I., Funahashi, Y., Shawber, C. J., Castrillon, D. H., Kollipara, R., DePinho, R. A., Kitajewski, J., & Accili, D. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32054 · Cited by 285 · cited 1× · see citing works
“FoxO1 null in muscle (HSA-Cre) Viable Normal growth, slow to fast switch in muscle [ 134 ,135]”
BackgroundContribution of satellite cells to IGF‐I induced hypertrophy of skeletal muscle
Barton‐Davis, Shoturma, & Sweeney (1999) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.1999.00618.x · Cited by 283 · cited 1× · see citing works
“Satellite cells were reported to play a crucial role in the hypertrophic response induced by viral-mediated gene transfer of IGF1 in adult mouse muscles, as shown by the fact that gamma-irradiation, used to block satellite-cell proliferation, was found to reduce the hypertrophic effect of IGF1 overexpression [ 107 ].”
BackgroundBAILYES, E. M., NAVÉ, B. T., Soos, M. A., ORR, S. R., Hayward, A. C., & Siddle, K. (1997) · Biochemical Journal · doi:10.1042/bj3270209 · Cited by 278 · cited 1× · see citing works
“No isoforms, but hybrids with insulin receptor are present in skeletal muscle [112]”
BackgroundRegulation of Muscle Mass by Follistatin and Activins
Lee, S.-J., Lee, Y.-S., Zimmers, T. A., Soleimani, A., Matzuk, M. M., Tsuchida, K., Cohn, R. D., & Barton, E. R. (2010) · Molecular Endocrinology · doi:10.1210/me.2010-0127 · Cited by 273 · cited 1× · see citing works
“In adult skeletal muscle, muscle hypertrophy can be induced and muscle wasting prevented by blocking myostatin either via postdevelopmental myostatin gene knockout, or with follistatin (a myostatin antagonist) or anti-myostatin antibodies or a soluble ActRIIB decoy receptor (see [19,20] and references therein).”
BackgroundMyosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3
Fielitz, J., Kim, M.-S., Shelton, J. M., Latif, S., Spencer, J. A., Glass, D. J., Richardson, J. A., Bassel‐Duby, R., & Olson, E. N. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32827 · Cited by 271 · cited 1× · see citing works
“By contrast, MuRF1 and 3 double-knockout mice develop skeletal and cardiac muscle myopathy with myosin accumulation [ 99 ], and MuRF1 and 2 doubleknockout mice have mild skeletal muscle hypertrophy and have reduced muscle loss during aging [100].”
BackgroundIGF-I restores satellite cell proliferative potential in immobilized old skeletal muscle
Chakravarthy, M. V., Davis, B. S., & Booth, F. W. (2000) · Journal of Applied Physiology · doi:10.1152/jappl.2000.89.4.1365 · Cited by 262 · see citing works
Hornberger, T. A., Stuppard, R., Conley, K. E., Fedele, M. J., Fiorotto, M. L., Chin, E. R., & Esser, K. A. (2004) · Biochemical Journal · doi:10.1042/bj20040274 · Cited by 256 · cited 1× · see citing works
“mTOR can also be directly activated independently of PI3K/Akt signaling, by phosphatidic acid, generated by phospholipase D (PLD) in response to mechanical signals induced by eccentric muscle contractions [ 27-29 ].”
BackgroundStructure/function relationships underlying regulation of FOXO transcription factors
Obšil, T., & Obšilová, V. (2008) · Oncogene · doi:10.1038/onc.2008.20 · Cited by 256 · see citing works
Spangenburg, E. E., Roith, D. L., Ward, C. W., & Bodine, S. C. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.141507 · Cited by 254 · see citing works
Li, H., Willis, M. S., Lockyer, P. P., Miller, N., McDonough, H., Glass, D. J., & Patterson, C. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31757 · Cited by 247 · cited 1× · see citing works
“In another feed-forward mechanism, MAFbx, which is activated by FoxO, acts in turn as coactivator of FoxO [9].”
BackgroundBlaauw, B., Canato, M., Agatea, L., Toniolo, L., Mammucari, C., Masiero, E., Abraham, R., Sandri, M., Schiaffino, S., & Reggiani, C. (2009) · The FASEB Journal · doi:10.1096/fj.09-131870 · Cited by 244 · cited 1× · see citing works
“MLC1f-myrAkt1, inducible Viable Muscle hypertrophy [82]”
Self-citationTNF‐related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle‐wasting cytokine
Dogra, C., Changoua, H., Wedhas, N., Qin, X., Wergedal, J. E., & Kumar, A. (2007) · The FASEB Journal · doi:10.1096/fj.06-7537com · Cited by 244 · cited 1× · see citing works
“Circulating cytokines, such as TNFa and TNF-related weak inducer of apoptosis (TWEAK), can activate MuRF1 via the transcription factor nuclear factor B( NFB) [32, 33 ].”
BackgroundBailey, J. L., Zheng, B., Hu, Z., Price, S. R., & Mitch, W. E. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2004100842 · Cited by 238 · cited 1× · see citing works
“IRS IRS1 and IRS2 [65,113]”
The hormonal action of IGF1 in postnatal mouse growth
Στρατικόπουλος, Η., Szabolcs, M. J., Dragatsis, I., Klinakis, A., & Efstratiadis, A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809223105 · Cited by 232 · cited 1× · see citing works
“However, this interpretation was challenged by the demonstration that conditional expression of IGF1 in the liver of an Igf1 null background contributes to about 30% of the adult body size [42].”
BackgroundO’Neil, T. K., Duffy, L. R., Frey, J. W., & Hornberger, T. A. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.173609 · Cited by 227 · see citing works
Cellular and molecular responses to increased skeletal muscle loading after irradiation.
Adams, G., Caiozzo, V., Haddad, F., & Baldwin, K. (2002) · American Journal of Physiology - Cell Physiology · doi:10.1152/ajpcell.00173.2002 · Cited by 227 · see citing works
Increased insulin sensitivity in mice lacking p85β subunit of phosphoinositide 3-kinase
Ueki, K., Yballe, C. M., Brachmann, S. M., Vicent, D., Watt, J. M., Kahn, C. R., & Cantley, L. C. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012581799 · Cited by 226 · cited 2× · see citing works
“PI3K p85a null mice have perinatal lethality, apparently due to liver necrosis [66], whereas PI3K p85b null mice are viable and have normal growth [ 67 ].”
BackgroundRas is involved in nerve-activity-dependent regulation of muscle genes
Murgia, M., Serrano, A. L., Calabria, E., Pallafacchina, G., Lømo, T., & Schiaffino, S. (2000) · Nature Cell Biology · doi:10.1038/35004013 · Cited by 218 · cited 1× · see citing works
“IGF1-dependent signaling via the mitogen-activated protein kinase/extracellular signal-regulated receptor kinase (MAPK/ERK) pathway has also been implicated in IGF1-dependent muscle growth regulation [56,57], however a constitutively active Ras double mutant that selectively activates the ERK pathway did not induce hy…”
BackgroundSelf-citationMavalli, M. D., DiGirolamo, D. J., Fan, Y., Riddle, R. C., Campbell, K. S., van Groen, T., Frank, S. J., Sperling, M. A., Esser, K. A., Bamman, M. M., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42447 · Cited by 213 · see citing works
Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals
Miyazaki, M., & Esser, K. A. (2008) · Journal of Applied Physiology · doi:10.1152/japplphysiol.91355.2008 · Cited by 197 · see citing works
Class I A Phosphoinositide 3-Kinase Regulates Heart Size and Physiological Cardiac Hypertrophy
Luo, J., McMullen, J. R., Sobkiw, C. L., Zhang, L., Dorfman, A. L., Sherwood, M. C., Logsdon, M. N., Horner, J. W., DePinho, R. A., Izumo, S., et al. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9491-9502.2005 · Cited by 197 · see citing works
Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia
Mora, A., Davies, A. M., Bertrand, L., Sharif, I., Budas, G. R., Jovanović, A., Mouton, V., Kahn, C. R., Lucocq, J. M., Gray, G. A., et al. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg469 · Cited by 196 · cited 2× · see citing works
“Conditional deletion of PDK1 in heart and muscle leads to dilated cardiomyopathy but no apparent change in muscle [ 73 ].”
BackgroundCooperative control of striated muscle mass and metabolism by MuRF1 and MuRF2
Witt, C. C., Witt, S. H., Lerche, S., Labeit, D., Back, W. E., & Labeit, S. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601952 · Cited by 186 · cited 1× · see citing works
“By contrast, MuRF1 and 3 double-knockout mice develop skeletal and cardiac muscle myopathy with myosin accumulation [99], and MuRF1 and 2 doubleknockout mice have mild skeletal muscle hypertrophy and have reduced muscle loss during aging [ 100 ].”
BackgroundMuscle Ring Finger 1, but not Muscle Ring Finger 2, Regulates Cardiac Hypertrophy In Vivo
Willis, M. S., Ike, C., Li, L., Wang, D.-Z., Glass, D. J., & Patterson, C. (2007) · Circulation Research · doi:10.1161/01.res.0000259559.48597.32 · Cited by 174 · cited 1× · see citing works
“A redundant function of the different MuRFs is suggested by the finding that mice lacking a single MuRF gene do not have a striking skeletal muscle phenotype [92, 97 ,98].”
BackgroundMyogenic Akt Signaling Regulates Blood Vessel Recruitment during Myofiber Growth
Takahashi, A., Kureishi, Y., Jiang, Y., Luo, Z., Guo, K. Y., Mukhopadhyay, D., Ivashchenko, Y., Branellec, D., & Walsh, K. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.13.4803-4814.2002 · Cited by 159 · cited 1× · see citing works
“c.a. Akt (via virus) Activation of Akt Muscle fiber hypertrophy [ 139 ]”
BackgroundGout, I. T., Minami, T., Hara, K., Tsujishita, Y., Filonenko, V. V., Waterfield, M. D., & Yonezawa, K. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.46.30061 · Cited by 148 · see citing works
Inhibition of MAP/ERK kinase prevents IGF-I-induced hypertrophy in rat muscles.
Haddad, F., & Adams, G. (2004) · Journal of applied physiology · doi:10.1152/japplphysiol.00856.2003 · Cited by 139 · cited 1× · see citing works
“IGF1-dependent signaling via the mitogen-activated protein kinase/extracellular signal-regulated receptor kinase (MAPK/ERK) pathway has also been implicated in IGF1-dependent muscle growth regulation [ 56 ,57], however a constitutively active Ras double mutant that selectively activates the ERK pathway did not induce…”
BackgroundPTEN Inhibition Improves Muscle Regeneration in Mice Fed a High-Fat Diet
Hu, Z., Wang, H., Lee, I. H., Modi, S., Wang, X., Du, J., & Mitch, W. E. (2010) · Diabetes · doi:10.2337/db09-1155 · Cited by 136 · cited 2× · see citing works
“Overload-induced skeletal muscle hypertrophy is also unaffected by PTEN knockout [70], but maturation of regenerating muscle fibers is accelerated [ 71 ].”
BackgroundImportant role for AMPKαl in limiting skeletal muscle cell hypertrophy
Mounier, R., Lantier, L., Leclerc, J., Sotiropoulos, A., Pende, M., Daegelen, D., Sakamoto, K., Foretz, M., & Viollet, B. (2009) · The FASEB Journal · doi:10.1096/fj.08-119057 · Cited by 133 · cited 1× · see citing works
“The role of AMPK in the control of muscle fiber size through mTOR inhibition is demonstrated by the phenotype of AMPKa1 knockout and AMPKa1/a2 double knockout mice, which develop muscle hypertrophy [25,26].”
BackgroundThe fate of newly formed satellite cells during compensatory muscle hypertrophy
Schiaffino, S., Pierobon Bormioli, S., & Aloisi, M. (1976) · Virchows Archiv B Cell Pathology · doi:10.1007/bf02899148 · Cited by 132 · cited 1× · see citing works
“Satellite-cell proliferation and fusion leading to increase in myonuclei occurs during postnatal muscle growth [110] and during compensatory hypertrophy induced by ablation of synergistic muscles [ 111 ], as demonstrated by electron microscope autoradiographs after 3 H-thymidine labeling.”
BackgroundSelf-citationFernandez, A. M., Dupont, J., Farrar, R. P., Lee, S., STANNARD, B. S., & Roith, D. L. (2002) · Journal of Clinical Investigation · doi:10.1172/jci13503 · Cited by 132 · cited 2× · see citing works
“IGF1 receptor 2 Viable Transient delay of postnatal muscle growth; unaffected overload-induced muscle hypertrophy; impaired muscle regeneration [ 59-62 ]”
BackgroundMichael, A., Haq, S., Chen, X., Hsich, E., Cui, L., Walters, B. M., Shao, Z., Bhattacharya, K., Kilter, H., Huggins, G. S., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401413200 · Cited by 131 · see citing works
Bayascas, J. R., Wullschleger, S., Sakamoto, K., García‐Martínez, J. M., Clacher, C., Komander, D., van Aalten, D. M. F., Boini, K. M., Lang, F. J. W., Lipina, C., et al. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.02032-07 · Cited by 131 · cited 1× · see citing works
“PDK1 knock-in mutant unable to bind phosphoinositides Viable Reduced growth (weight 35% of control) [ 125 ]”
BackgroundAoyama, T., Matsui, T., Novikov, M., Park, J., Hemmings, B. A., & Rosenzweig, A. (2005) · Circulation · doi:10.1161/01.cir.0000160352.58142.06 · Cited by 128 · cited 1× · see citing works
“SGK1 is activated by IGF1, PI3K and PDK1, and can induce phosphorylation of S6K and GSK3b in cardiomyocytes [54] and phosphorylation of FoxO3 in various cell types [55].”
BackgroundThe ABCs of IGF-I isoforms: impact on muscle hypertrophy and implications for repair
Barton, E. R. (2006) · Applied Physiology Nutrition and Metabolism · doi:10.1139/h06-054 · Cited by 126 · cited 2× · see citing works
“Two isoforms, IGF1A and IGF1B, are found in most mammals, and an additional form, IGF1C, is present in primates and humans [49].”
BackgroundCsibi, A., Cornille, K., Leibovitch, M.-P., Anne Poupon, B., Tintignac, L. A. J., Sanchez, A. M. J., & Leibovitch, S. A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008994 · Cited by 121 · cited 1× · see citing works
“MAFbx also appears to control protein synthesis by ubiquitylating and thus promoting the degradation of the eukariotic translation initiation factor 3 subunit F (eIF3F), thus suppressing S6K1 activation by mTOR [10,11].”
BackgroundGoodman, C. A., Miu, M. H., Frey, J. W., Mabrey, D. M., Lincoln, H. C., Ge, Y., Chen, J., & Hornberger, T. A. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-05-0454 · Cited by 120 · see citing works
Wang, H.-V., Chang, L.-W., Brixius, K., Wickström, S. A., Montanez, E., Thievessen, I., Schwander, M., Müller, U., Bloch, W., Mayer, U., et al. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200707175 · Cited by 112 · cited 1× · see citing works
“Mechanical signals via integrin b 1a nd integrin-linked kinase (ILK) lead to phosphorylation of the IGF1 receptor and activation of the PI3K-Akt pathway in muscle cells [ 13 ].”
BackgroundCoordinated maintenance of muscle cell size control by AMP‐activated protein kinase
Lander, L., Mourner, R., Leclerc, J., Pende, M., Foretz, M., & Viollet, B. (2010) · The FASEB Journal · doi:10.1096/fj.10-155994 · Cited by 108 · cited 1× · see citing works
“The role of AMPK in the control of muscle fiber size through mTOR inhibition is demonstrated by the phenotype of AMPKa1 knockout and AMPKa1/a2 double knockout mice, which develop muscle hypertrophy [25,26].”
BackgroundCriswell, D. S., Booth, F. W., DeMayo, F. J., Schwartz, R. J., Gordon, S. E., & Fiorotto, M. L. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.275.3.e373 · Cited by 101 · cited 2× · see citing works
“IGF1 concentration in the serum was similar in wild-type and transgenic mice, but transgenic mice developed skeletal muscle hypertrophy [45-47].”
BackgroundA growth stimulus is needed for IGF-1 to induce skeletal muscle hypertrophy in vivo
Shavlakadze, T., Chai, R. J., Maley, K., Cozens, G. S., Grounds, G., Winn, N., Rosenthal, N. A., & Grounds, M. D. (2010) · Journal of Cell Science · doi:10.1242/jcs.061119 · Cited by 99 · cited 1× · see citing works
“This interpretation would be consistent with the view that a growth stimulus is required for IGF1 to induce muscle hypertrophy in vivo [ 109 ].”
ResultMitogen-activated protein kinase signaling is necessary for the maintenance of skeletal muscle mass
Shi, H., Scheffler, J. M., Zeng, C., Pleitner, J. M., Hannon, K., Grant, A. L., & Gerrard, D. E. (2009) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00475.2008 · Cited by 99 · cited 1× · see citing works
“IGF1-dependent signaling via the mitogen-activated protein kinase/extracellular signal-regulated receptor kinase (MAPK/ERK) pathway has also been implicated in IGF1-dependent muscle growth regulation [56,57], however a constitutively active Ras double mutant that selectively activates the ERK pathway did not induce hy…”
BackgroundFielitz, J., van Rooij, E., Spencer, J. A., Shelton, J. M., Latif, S., van der Nagel, R., Bezprozvannaya, S., Windt, L. J. D., Richardson, J. A., Bassel‐Duby, R., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611726104 · Cited by 97 · cited 1× · see citing works
“A redundant function of the different MuRFs is suggested by the finding that mice lacking a single MuRF gene do not have a striking skeletal muscle phenotype [92,97, 98 ].”
BackgroundAl‐Zghoul, M. B., Gerrard, D. E., Watkins, B. A., & Hannon, K. (2003) · The FASEB Journal · doi:10.1096/fj.03-0293fje · Cited by 96 · cited 1× · see citing works
“Igf1 Overexpression of Igf1 Prevention of glucocorticoid-induced muscle atrophy [48, 138 ]”
BackgroundSchakman, O., Gilson, H., de Coninck, V., Lause, P., Verniers, J., Havaux, X., Ketelslegers, J., & Thissen, J. (2005) · Endocrinology · doi:10.1210/en.2004-1594 · Cited by 95 · cited 3× · see citing works
“In adult rats, local infusion of recombinant IGF1 results in muscle hypertrophy [104,105] and plasmid-mediated IGF1 gene transfer prevents corticosteroid-induced muscle atrophy [ 48 ].”
BackgroundInfluentialNebulin and N-WASP Cooperate to Cause IGF-1–Induced Sarcomeric Actin Filament Formation
Takano, K., Watanabe‐Takano, H., Suetsugu, S., Kurita, S., Tsujita, K., Kimura, S., Karatsu, T., Takenawa, T., & Endo, T. (2010) · Science · doi:10.1126/science.1197767 · Cited by 90 · see citing works
Wu, Y., Sun, H., Yakar, S., & LeRoith, D. (2009) · Endocrinology · doi:10.1210/en.2009-0272 · Cited by 83 · cited 1× · see citing works
“In a similar study, elevated serum concentrations of IGF1, induced by overexpressing a rat Igf1 transgene specifically in the liver of Igf1 null mice, were able to rescue the severe growth-retarded phenotype observed in these mice [44].”
BackgroundBlaauw, B., Mammucari, C., Toniolo, L., Agatea, L., Abraham, R., Sandri, M., Reggiani, C., & Schiaffino, S. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn264 · Cited by 83 · cited 1× · see citing works
“Akt activation causes multiple changes in muscle gene expression, documented by microarray analyses [80,82, 83 ].”
BackgroundSelf-citationBarton, E. R., DeMeo, J., & Lei, H. (2010) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01308.2009 · Cited by 78 · cited 3× · see citing works
“The E peptides appear to be essential for muscle growth regulation because viral delivery of IGF1A or IGF1B promoted functional hypertrophy in mouse muscles, whereas delivery of mature IGF1 devoid of E peptide failed to cause an increase in muscle mass [ 50 ].”
BackgroundInfluentialSchakman, O., Kalista, S., Bertrand, L., Lause, P., Verniers, J., Ketelslegers, J. M., & Thissen, J. (2008) · Endocrinology · doi:10.1210/en.2008-0439 · Cited by 78 · cited 1× · see citing works
“Finally, corticosteroids inhibit the IGF1-Akt pathway by acting at multiple levels, such as inducing decreased production of IGF1 and increased production of myostatin [34].”
BackgroundHamilton, D. L., Philp, A., MacKenzie, M. G., & Baar, K. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011624 · Cited by 71 · see citing works
Persistent IGF‐I overexpression in skeletal muscle transiently enhances DNA accretion and growth 1
Fiorotto, M. L., Schwartz, R. J., & Delaughter, M. C. (2003) · The FASEB Journal · doi:10.1096/fj.02-0289fje · Cited by 69 · see citing works
The cathepsin L gene is a direct target of FOXO1 in skeletal muscle
Yamazaki, Y., Kamei, Y., Sugita, S., Akaike, F., Kanai, S., Miura, S., Hirata, Y., Troen, B. R., Kitamura, T., Nishino, I., et al. (2010) · Biochemical Journal · doi:10.1042/bj20091346 · Cited by 63 · cited 1× · see citing works
“FoxO1 null in muscle (HSA-Cre) Viable Normal growth, slow to fast switch in muscle [134, 135 ]”
BackgroundDurieux, A., D’Antona, G., Dominique Desplanches, C., Freyssenet, D. G., Klossner, S., Bottinelli, R., & Flück, M. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.171355 · Cited by 62 · cited 1× · see citing works
“Overexpression of FAK by electrotransfer was found to induce slight hypertrophy in adult rat muscles, but the effect on the IGF1-Akt pathway was not investigated [14].”
BackgroundPilot‐Storck, F., Chopin, E., Rual, J.-F. M., Baudot, A., Dobrokhotov, P., Robinson‐Rechavi, M., Brun, C., Cusick, M. E., HILL, D. E., Schaeffer, L., et al. (2010) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m900568-mcp200 · Cited by 57 · cited 1× · see citing works
“Indeed, a recent interactome map based on a yeast two-hybrid screen for 33 components of the PI3K-mTOR pathway has identified 802 interactions, including 67 new validated interactions [36].”
BackgroundCloning and Characterization of p70S6KβDefines a Novel Family of p70 S6 Kinases
Saitoh, M., ten Dijke, P., Miyazono, K., & Ichijo, H. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.9784 · Cited by 51 · cited 1× · see citing works
“S6K S6K1 and S6K2 [117-119]”
Héron‐Milhavet, L., Mamaeva, D. V., LeRoith, D., Lamb, N. J. C., & Fernandez, A. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22218 · Cited by 32 · see citing works
Tang, Z., Yu, R., Lu, Y., Parlow, A. F., & Liu, J. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00494.2004 · Cited by 22 · cited 1× · see citing works
“This discrepancy was explained by the fact that a residual fraction of circulating IGF1 is detected in the liver-specific knockout [40,41] because of incomplete Igf1 gene excision [ 43 ].”
BackgroundCohen, S., Brault, J. J., Gygi, S. P., Glass, D. J., Valenzuela, D. M., Gartner, C. A., Latres, E., & Goldberg, A. L. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem2067oia13 · Cited by 20 · see citing works
Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy
Risson, V., Mazelin, L., Roceri, M., Sanchez, H., Moncollin, V., Corneloup, C., Richard‐Bulteau, H., Vignaud, A., Baas, D., Defour, A., et al. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem20613oia33 · Cited by 17 · see citing works
Blaauw, B., Canato, M., Agatea, L., Toniolo, L., Mammucari, C., Masiero, E., Abraham, R., Sandri, M., Schiaffino, S., & Reggiani, C. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2009.12.823 · Cited by 17 · see citing works
Self-citationMiller, N., Willis, M. S., Li, H., McDonough, H., Glass, D. J., Lockyer, P. P., & Patterson, C. (2020) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/e39n-kz48 · Cited by 12 · see citing works
Regulation of Muscle Mass by Follistatin and Activins
Lee, S., Lee, Y., Zimmers, T. A., Soleimani, A. A., Matzuk, M. M., Tsuchida, K., Cohn, R. D., & Barton, E. R. (2010) · Endocrine Reviews · doi:10.1210/edrv.31.5.9985 · Cited by 9 · see citing works
Fernandez, A. M., Dupont, J., Farrar, R. P., Lee, S., STANNARD, B. S., & Roith, D. L. (2002) · Journal of Clinical Investigation · doi:10.1172/jci200213503 · Cited by 7 · see citing works
Persistent IGF-I overexpression in skeletal muscle transiently enhances DNA accretion and growth
Fiorotto, M. L. (2002) · The FASEB Journal · doi:10.1096/fj.02-0189fje · Cited by 5 · cited 2× · see citing works
“ASA-hIGF1 Viable Muscle hypertrophy [45,47]”
BackgroundA growth stimulus is needed for IGF-1 to induce skeletal muscle hypertrophy in vivo
Shavlakadze, T., Chai, J., Maley, K., Cozens, G. S., Grounds, G., Winn, N., Rosenthal, N. A., & Grounds, M. D. (2013) · Journal of Cell Science · doi:10.1242/jcs.141143 · Cited by 4 · see citing works
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Mechanisms regulating skeletal muscle growth and atrophy
Schiaffino, S., Dyar, K. A., Ciciliot, S., Blaauw, B., & Sandri, M. (2013) · The FEBS Journal · doi:10.1111/febs.12253 · Cited by 1,492 · see citing works
Self-citationCellular and molecular mechanisms of muscle atrophy
Bonaldo, P., & Sandri, M. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.010389 · Cited by 1,284 · see citing works
“Insulin-like growth factor 1 (IGF1), a circulating growth factor, is also produced locally by many tissues, including skeletal muscle (reviewed in Schiaffino and Mammucari, 2011).”
Muscle wasting in disease: molecular mechanisms and promising therapies
Cohen, S., Nathan, J. A., & Goldberg, A. L. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4467 · Cited by 1,089 · see citing works
A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy
Ruas, J. L., White, J. P., Rao, R. R., Kleiner, S., Brannan, K. T., Harrison, B. C., Greene, N. P., Wu, J., Estall, J. L., Irving, B. A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.050 · Cited by 677 · see citing works
Skeletal muscle: A review of molecular structure and function, in health and disease
Mukund, K., & Subramaniam, S. (2019) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1462 · Cited by 680 · see citing works
“The major signaling pathway that regulates muscle mass and protein synthesis is the IGF1-Akt/PKB-mTOR signaling pathway (Schiaffino & Mammucari, 2011; Figure 12).”
BackgroundFrailty and sarcopenia: The potential role of an aged immune system
Wilson, D., Jackson, T., Sapey, E., & Lord, J. M. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.01.006 · Cited by 573 · see citing works
“Studies in rodents suggest that muscle synthesis is intrinsically linked with muscle atrophy via the PI3k-Akt pathway which is central to both processes (Schiaffino and Mammucari, 2011).”
mTOR as a key regulator in maintaining skeletal muscle mass
Yoon, M.-S. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00788 · Cited by 495 · see citing works
“In addition, Akt regulates muscle mass by phosphorylating and deactivating glycogen synthase kinase (GSK) β1, followed by the GSK β1-dependent inhibition of the eukaryotic translation initiation factor 2B (eIF2B) (Manning and Cantley, 2007; Schiaffino and Mammucari, 2011).”
BackgroundMolecular Choreography of Acute Exercise
Contrepois, K., Wu, S., Moneghetti, K. J., Hornburg, D., Ahadi, S., Tsai, M.-S., Metwally, A. A., Wei, E., Lee-McMullen, B., Quijada, J. V., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.043 · Cited by 502 · see citing works
Muscle wasting and cachexia in heart failure: mechanisms and therapies
von Haehling, S., Ebner, N., dos Santos, M. R., Springer, J., & Anker, S. D. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.51 · Cited by 427 · see citing works
Muscle and bone, two interconnected tissues
Tagliaferri, C., Wittrant, Y., Davicco, M.-J., Walrand, S., & Coxam, V. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.03.002 · Cited by 391 · see citing works
Atrogin-1, MuRF-1, and sarcopenia
Gumucio, J. P., & Mendias, C. L. (2012) · Endocrine · doi:10.1007/s12020-012-9751-7 · Cited by 368 · see citing works
Dzik, K. P., & Kaczor, J. J. (2019) · European Journal of Applied Physiology · doi:10.1007/s00421-019-04104-x · Cited by 357 · see citing works
Sandri, M., Barberi, L., Bijlsma, A. Y., Blaauw, B., Dyar, K. A., Milan, G., Mammucari, C., Meskers, C. G. M., Pallafacchina, G., Paoli, A., et al. (2013) · Biogerontology · doi:10.1007/s10522-013-9432-9 · Cited by 340 · see citing works
Self-citationHuman skeletal muscle possesses an epigenetic memory of hypertrophy
Seaborne, R. A., Strauss, J., Cocks, M., Shepherd, S., O’Brien, T. D., van Someren, K. A., Bell, P. G., Murgatroyd, C., Morton, J. P., Stewart, C. E., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-20287-3 · Cited by 334 · see citing works
“Importantly, following reloading induced muscle growth we observed an increase in the number of epigenetically modified sites (27,155) and an enhanced number of hypomethylated DNA sites (18,816, Fig.”
BackgroundMolecular circuitry of stem cell fate in skeletal muscle regeneration, ageing and disease
Almada, A. E., & Wagers, A. J. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.7 · Cited by 314 · see citing works
Myostatin/activin pathway antagonism: molecular basis and therapeutic potential
Han, H. Q., Zhou, X., Mitch, W. E., & Goldberg, A. L. (2013) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.05.019 · Cited by 314 · see citing works
Vanweert, F., Schrauwen, P., & Esther Phielix, E. (2022) · Nutrition and Diabetes · doi:10.1038/s41387-022-00213-3 · Cited by 315 · see citing works
Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy
Cullup, T., Kho, A. L., Dionisi‐Vici, C., Brandmeier, B., Smith, F., Urry, Z., Simpson, M. A., Yau, S., Bertini, E., McClelland, V. M., et al. (2012) · Nature Genetics · doi:10.1038/ng.2497 · Cited by 282 · see citing works
“To see if these changes also involve upstream regulatory mechanisms of autophagy, we analysed the AKT-mTOR protein kinase pathway, a major pathway controlling the expression of autophagy proteins by inhibiting the transcriptional activity of FoxO transcription factors 35 .”
Muscle injuries and strategies for improving their repair
Laumonier, T., & Ménétrey, J. (2016) · Journal of Experimental Orthopaedics · doi:10.1186/s40634-016-0051-7 · Cited by 276 · see citing works
“IGF-I stimulates myoblasts proliferation and differentiation (Engert et al. 1996) and is implicated in the regulation of muscle growth (Schiaffino and Mammucari 2011).”
BackgroundMuscle Atrophy Induced by Mechanical Unloading: Mechanisms and Potential Countermeasures
Gao, Y., Arfat, Y., Wang, H., & Goswami, N. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00235 · Cited by 275 · see citing works
“Under normal physiological condition, the IGF-1-Akt-mTOR pathway acts as a key regulator in the translation initiation step of protein synthesis in skeletal muscle (Erbay et al., 2003; Han et al., 2008; Schiaffino and Mammucari, 2011).”
BackgroundEgan, B., & Sharples, A. P. (2023) · Physiological Reviews · doi:10.1152/physrev.00054.2021 · Cited by 278 · see citing works
Caloric restriction mimetics: towards a molecular definition
Madeo, F., Pietrocola, F., Eisenberg, T., & Kroemer, G. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4391 · Cited by 264 · see citing works
Mechanisms Modulating Skeletal Muscle Phenotype
Blaauw, B., Schiaffino, S., & Reggiani, C. (2013) · Comprehensive physiology · doi:10.1002/cphy.c130009 · Cited by 278 · see citing works
Self-citationStress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy
Ebert, S. M., Dyle, M. C., Kunkel, S. D., Bullard, S. A., Bongers, K. S., Fox, D. K., Dierdorff, J. M., Foster, E. D., & Adams, C. M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.374777 · Cited by 221 · see citing works
Roberts, M. D., McCarthy, J. J., Hornberger, T. A., Phillips, S. M., Mackey, A. L., Nader, G. A., Boppart, M. D., Kavazis, A. N., Reidy, P. T., Ogasawara, R., et al. (2023) · Physiological Reviews · doi:10.1152/physrev.00039.2022 · Cited by 214 · see citing works
Genomic basis for the convergent evolution of electric organs
Gallant, J. R., Traeger, L. L., Volkening, J. D., Moffett, H. F., Chen, P.-H., Novina, C. D., Phillips, G. N., Anand, R., Wells, G. B., Pinch, M., et al. (2014) · Science · doi:10.1126/science.1254432 · Cited by 207 · see citing works
Fibro-adipogenic progenitors in skeletal muscle homeostasis, regeneration and diseases
Molina, T., Fabre, P., & Dumont, N. A. (2021) · Open Biology · doi:10.1098/rsob.210110 · Cited by 193 · see citing works
Luo, L., Lu, A.-M., Wang, Y., Hong, A., Chen, Y., Hu, J., Li, X., & Qin, Z.-H. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2013.02.009 · Cited by 192 · see citing works
Gehlert, S., Bloch, W., & Suhr, F. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16011066 · Cited by 190 · see citing works
The Mitochondrial Calcium Uniporter Controls Skeletal Muscle Trophism In Vivo
Mammucari, C., Gherardi, G., Zamparo, I., Raffaello, A., Boncompagni, S., Chemello, F., Cagnin, S., Braga, A., Zanin, S., Pallafacchina, G., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.01.056 · Cited by 190 · see citing works
“Specific AKT downstream targets were phosphorylated: in detail, 4E-BP1 and GSK3β, two inhibitors of protein translation (Schiaffino and Mammucari, 2011), were phosphorylated, and thus inhibited, in AAV-MCU muscles (Figure 3M).”
BackgroundSelf-citationLncIRS1 controls muscle atrophy via sponging miR‐15 family to activate IGF1‐PI3K/AKT pathway
Li, Z., Cai, B., Abdalla, B. A., Zhu, X., Zheng, M., Han, P., Nie, Q., & Zhang, X. (2019) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12374 · Cited by 190 · see citing works
“IGF1-PI3K/AKT pathway is a key intracellular signalling mechanism controlling muscle hypertrophy.(7) In addition, evidence suggests that in complex organism development, RNA contains a hidden layer of regulatory information.”
BackgroundInfluentialUpdate on the effects of microgravity on the musculoskeletal system
Juhl, O. J., Buettmann, E. G., Friedman, M. A., DeNapoli, R. C., Hoppock, G. A., & Donahue, H. J. (2021) · npj Microgravity · doi:10.1038/s41526-021-00158-4 · Cited by 190 · see citing works
Regulation of Skeletal Muscle Glucose Transport and Glucose Metabolism by Exercise Training
Evans, P. L., McMillin, S. L., Weyrauch, L. A., & Witczak, C. A. (2019) · Nutrients · doi:10.3390/nu11102432 · Cited by 190 · see citing works
“Akt1 is a kinase found in skeletal muscle that plays a critical role in mediating resistance exercise training-induced muscle hypertrophic growth and protein synthesis (reviewed in [208,209]).”
BackgroundDifferential role of insulin/IGF-1 receptor signaling in muscle growth and glucose homeostasis
O’Neill, B. T., Lauritzen, H. P. M. M., Hirshman, M. F., Smyth, G., Goodyear, L. J., & Kahn, C. R. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.04.037 · Cited by 173 · see citing works
“It has been known for some time that IGF-1 treatment can induce muscle hypertrophy via the Akt-mTOR pathways, yet previous studies have indicated that deletion of IGF1Rs alone in muscle only modestly changes myocyte size and morphology (Schiaffino and Mammucari, 2011; Mavalli et al., 2010).”
Pala, F., Di Girolamo, D., Mella, S., Yennek, S., Chatre, L., Ricchetti, M., & Tajbakhsh, S. (2018) · Journal of Cell Science · doi:10.1242/jcs.212977 · Cited by 184 · see citing works
“Depending on their fibre composition (fast type II and slow type I fibres), different muscles exhibit more glycolytic or oxidative activity (Schiaffino and Mammucari, 2011).”
BackgroundInsulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis
O'Neill, B. T., Lee, K. Y., Klaus, K. A., Softic, S., Krumpoch, M. T., Fentz, J., Stanford, K. I., Robinson, M. M., Cai, W., Kleinridders, A., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86522 · Cited by 182 · see citing works
Role of satellite cells in muscle growth and maintenance of muscle mass
Pallafacchina, G., Blaauw, B., & Schiaffino, S. (2012) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2012.02.002 · Cited by 173 · see citing works
Self-citationThe Role of Reactive Oxygen Species in the Life Cycle of the Mitochondrion
Venditti, P., & Meo, S. D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21062173 · Cited by 170 · see citing works
Schwalm, C., Jamart, C., Benoit, N., Naslain, D., Prémont, C., Prévet, J., Thienen, R. V., Deldicque, L., & Francaux, M. (2015) · The FASEB Journal · doi:10.1096/fj.14-267187 · Cited by 174 · see citing works
“Indeed, beyond muscle damage, autophagy can be activated while the energetic status of the cell is impaired or in response to changes in hormonal environment (21, 22).”
BackgroundMolecular Mechanisms of Skeletal Muscle Hypertrophy
Schiaffino, S., Reggiani, C., Akimoto, T., & Blaauw, B. (2020) · Journal of Neuromuscular Diseases · doi:10.3233/jnd-200568 · Cited by 169 · see citing works
Self-citationSarcopenia and Cognitive Decline in Older Adults: Targeting the Muscle–Brain Axis
Arosio, B., Calvani, R., Ferri, E., Coelho-Junior, H. J., Carandina, A., Campanelli, F., Ghiglieri, V., Marzetti, E., & Picca, A. (2023) · Nutrients · doi:10.3390/nu15081853 · Cited by 165 · see citing works
“The PI3K–AKT–mTOR pathway is activated by this protein’s interaction with the insulin receptor substrate 1 (IRS1), which enhances muscle protein synthesis and prevents protein degradation [73].”
BackgroundInsulin-Like Growth Factor-1 Receptor Is Regulated by microRNA-133 during Skeletal Myogenesis
Huang, M., Xu, H. M., Xie, S., Zhou, H., & Qu, L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0029173 · Cited by 165 · see citing works
“phosphorylation of Akt, which plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, differentiation, growth and apoptosis [25,26].”
BackgroundOno, Y., Maejima, Y., Saito, M., Sakamoto, K., Horita, S., Shimomura, K., Inoue, S., & Kotani, J. (2020) · Scientific Reports · doi:10.1038/s41598-020-57714-3 · Cited by 164 · see citing works
CURRENT NUTRITIONAL RECOMMENDATIONS AND NOVEL DIETARY STRATEGIES TO MANAGE SARCOPENIA
Calvani, R., Miccheli, A., Landi, F., Bossola, M., Cesari, M., Leeuwenburgh, C., Sieber, C. C., Bernabei, R., & Marzetti, E. (2013) · The Journal of Frailty & Aging · doi:10.14283/jfa.2013.7 · Cited by 163 · see citing works
Antioxidant and Adaptative Response Mediated by Nrf2 during Physical Exercise
Vargas-Mendoza, N., Morales‐González, Á., Madrigal‐Santillán, E., Madrigal‐Bujaidar, E., Álvarez‐González, I., García-Melo, L. F., Anguiano‐Robledo, L., Fregoso-Aguilar, T. A., & Morales‐González, J. A. (2019) · Antioxidants · doi:10.3390/antiox8060196 · Cited by 163 · see citing works
“Simultaneously, the activation of PGC-1α4 also promotes the synthesis of IGF-1, intervening in the formation of muscle mass [107].”
BackgroundInfluentialCell therapy to improve regeneration of skeletal muscle injuries
Qazi, T. H., Duda, G. N., Ort, M., Perka, C., Geißler, S., & Winkler, T. (2019) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12416 · Cited by 160 · see citing works
Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals
Segalés, J., Perdiguero, E., Serrano, A. L., Sousa-Victor, P., Ortet, L., Jardí, M., Budanov, A. V., Garcia-Prat, L., Sandri, M., Thomson, D. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13832-9 · Cited by 153 · see citing works
Bone and skeletal muscle: Key players in mechanotransduction and potential overlapping mechanisms
Goodman, C. A., Hornberger, T. A., & Robling, A. G. (2015) · Bone · doi:10.1016/j.bone.2015.04.014 · Cited by 155 · see citing works
“stages of growth and development and under various conditions that may include increased mechanical loading (for recent reviews on these topics, see [32–41]).”
BackgroundBarclay, R. D., Burd, N. A., Tyler, C. J., Tillin, N. A., & Mackenzie, R. W. (2019) · Frontiers in Nutrition · doi:10.3389/fnut.2019.00146 · Cited by 152 · see citing works
Myogenin is an essential regulator of adult myofibre growth and muscle stem cell homeostasis
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Glucocorticoid Signaling: An Update from a Genomic Perspective
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“In physiologic muscle growth, insulin growth factor (IGF)-1 is commonly implicated as an upstream signal (Schiaffino and Mammucari, 2011), but the effects of CDC exosomes onmdx soleus muscle were independent of IGF-1 receptors (Figure 5E).”
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“the direct activation of mTORC1, further upstream activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by IGF-1 is also sufficient to activate rapamycin-sensitive mTORC1 signaling, increase protein synthesis, and induce skeletal muscle hypertrophy (28, 81).”
BackgroundInteraction Between Bone and Muscle in Older Persons with Mobility Limitations
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“The Akt-mTOR pathway is central to the regulation of muscle mass because it promotes protein synthesis and inhibits protein degradation (Schiaffino & Mammucari, 2011).”
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“IGF1 plays a similar role in glucose metabolism as insulin (Schiaffino and Mammucari, 2011).”
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“This finding suggests the role of obesity as a positive modulator of IL-6R and IL-6 expression in adipose tissue (Sindhu et al., 2015).”
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“However, the exact mechanisms that lead to muscle growth, even for very well-characterised signals with long-established roles, such as the insulin-like growth factor (IGF) family (Schiaffino and Mammucari 2011), remain to be established.”
BackgroundSestrins are evolutionarily conserved mediators of exercise benefits
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“breviflora(117), decumbesterone A (157)(118) and ajugacetalsterone E (158)(119) isolated from Ajuga decumbens, 22-dehydrocyasterone-2glucoside (159), ajugacetalsterone A (160) and ajugacetalsterone B (161), isolated from Ajuga nipponensis(120), 25-hydroxy-atrotosterone A (162), 11-hydroxy-cyasterone (163), 11-hydroxys…”
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“nutrients, and mechanical loading to regulate protein synthesis.(91,92,97) Growth”
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“Muscle protein synthesis following exercise is mainly controlled by mTORC1 (Bodine et al., 2001; Schiaffino and Mammucari, 2011).”
BackgroundInfluentialAutophagy as a Potential Target for Sarcopenia: AUTOPHAGY REGULATION IN SARCOPENIA
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“For instance, the activation of Akt signaling by insulin or IGF-1 inactivates FoxO-dependent transcription (Schiaffino and Mammucari, 2011), and mice with the musclespecific loss of IGF-1 receptor have reduced mass and fiber number of skeletal muscle (Mavalli et al., 2010), suggesting that…”
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“The IGF1/PI3K/AKT/mTOR signalling pathway is activated by several factors under various conditions such as growth, glucose homeostasis regulators and/or muscle atrophy/hypertrophy factors that are especially secreted during resistance training [45].”
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“Skeletal muscle bulk is determined by the net effect of hypertrophy and atrophy processes: protein synthesis and degradation (comprising atrophy and autophagy) (reviewed in Schiaffino and Mammucari, 2011).”
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“However, although the IGF-1/ AKT/PI3K pathway is obligatory for hypertrophy during human maturation, the extent of its involvement in muscular adaptations to regimented RT remains unclear (33).”
BackgroundSarcopenia, cachexia, and muscle performance in heart failure: Review update 2016
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- Authors
- Schiaffino, S., & Mammucari, C.
- Affiliations
- Veneto Institute of Molecular Medicine (IT)
- University of Padua (IT)
- Corresponding author
- Schiaffino, Stefano
- Venue
- Skeletal Muscle
- Published
- 2011
- Volume
- 1
- Issue
- 1
- Pages
- 4
- ISSN
- 2044-5040 (ISSN-L)
- PMC
- PMC3143906
- OpenAlex
- W2150059080
- Cited by
- 816
- References
- 150
- Citations by year
- 2026: 42 · 2025: 70 · 2024: 68 · 2023: 63 · 2022: 55 · 2021: 59 · 2020: 56 · 2019: 69 · 2018: 68 · 2017: 57 · 2016: 42 · 2015: 46 · 2014: 48 · 2013: 44 · 2012: 23
- FWCI
- 15.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Skeletal Muscle (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- European Commission
- Università degli Studi di Padova
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- skeletal muscle growth, IGF-1 signaling, mTOR, GSK3β, FOXO transcription factors, muscle regeneration, myogenesis, mechanical loading, muscle atrophy, muscle protein synthesis, protein degradation
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