The role of AMPK and PGC-1α in the regulation of muscle mass

El papel del AMPK y el PGC-1α en la regulación de la masa muscular


Bacharel em Educação Física pela UNIMEP

Mestre em Ciências da Motricidade pela UNESP


Prof. Ms. André Katayama Yamada







          Skeletal muscle mass is orchestrated by fine mechanisms involving the equilibrium between rates of protein synthesis and degradation. Protein synthesis is increased by activation of anabolic pathways such as IGF-1 and mTOR. Recently, molecules involved in mitochondrial biogenesis also demonstrate to play a key role in muscle mass regulation. AMPK and PGC-1α emerge now as important mediators in the control of skeletal muscle mass.

          Keywords: Muscle mass. AMPK. PGC-1α.


EFDeportes.com, Revista Digital. Buenos Aires, Año 18, Nº 183, Agosto de 2013. http://www.efdeportes.com

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    Molecular biology improved the way scientists understand skeletal muscle biology (COFFEY & HAWLEY, 2007; BALDWIN & HADDAD, 2010; NADER, 2006; WACKERHAGE e RATCKEVICIUS, 2008). A wide range of anabolic and catabolic molecules were determined recently (SANDRI, 2008; GLASS, 2003). The signaling pathways function like a network all interconnected, a mechanism denominated cross-talk (GLASS, 2011). Thus, the concept that a single protein is responsible for the phenotype is not plausible anymore (ADAMS & HADDAD, 1996). Recently, a body of evidence is demonstrating that molecules involved in energy status have an enormous potential to regulate skeletal muscle mass (AGUILAR et al., 2007; MOURNIER et al., 2009; LANTIER et al., 2010; SANDRI et al., 2006; HANDSCHIN et al., 2007). For example, elevations in protein kinase activated by AMP (AMPK) are observed in extreme cases of energy expenditure, like in long duration exercise (LEE-YANG et al., 2009). AMPK stimulates mitochondrial genome reprogramming that triggers oxidative adjustments (HARDIE, 2011). This probably results in blockade of a protein synthesis kinase named mTORC1 (MOUNIER et al., 2011). PGC-1α plays important role in mitochondrial gene expression and increases in mitochondrial DNA in skeletal muscle (FERNANDEZ-MARCOS & AUWERX, 2011). PGC-1α seems to protect muscle integrity, mainly the deleterious condition of muscle atrophy (SANDRI et al., 2006)


    Protein kinase activated by AMPK (AMPK) is a heterotrimeric protein threonine/kinase composed by a catalytic region and two regulatory subunits (STEINBERG & KEMP, 2009). AMPK monitors energy homeostasis and is activated when the AMP/ATP rates increase (HARDIE, 2011). Stressor conditions like exercise, fasting and mitochondrial dysfunctions increase the activity of this molecule (LEE-YANG et al., 2009; CHING et al., 2010; ROMANELLO et al., 2010). AMPK is recognized by its catabolic effect, because inhibit protein synthesis (STEINBERG & KEMP, 2009). The inactive expression of AMPK induces increase in muscle mass under in vivo condition. (AGUILAR et al., 2007). Knock-out deletion models of AMPK induces hypertrophy either in vivo and in vitro (LANTIER et al., 2010; MOUNIER et al., 2009). AICAR (selective drug utilized by diabetics patients and that activates AMPK) results in muscle atrophy (TONG et al., 2009). More fascinating is the study that demonstrated that muscles deficient for p70S6K1 (marker of hypertrophy) presents elevated levels of AMPK and muscle atrophy. Inhibition of AMPK in these cells restores cell growth (AGUILAR et al., 2007). AMPK blocks proteins involved in protein synthesis like mTORC1 (MOUNIER et al., 2009). The possible mechanisms of inhibition is the phosphorylation of tuberous sclerosis complex (TSC2), resulting in activation of Rheb, which can inhibit mTORC1 (MOUNIER et al., 2011). Other possibility is by Raptor dissociation with mTORC1 (GWINN et al., 2008). Increases in AMPK are associated with increases also in MuRF1 and Atrogin-1 (genes involved in atrophy), and this mechanism is dependent of increased nuclear FoxO (KRAWIEC et al., 2007). A doubt that remains is if why activation of AMPK induces atrophy and blocks mTOR and continues to have benefits, while increase in muscle mass concomitant with elevations in mTOR is related to improved metabolism and better muscle function.

    The peroxisome proliferator co activator 1 receptor (PGC-1α) is a transcriptional co activator (HANDSCHIN, 2010). PGC-1α was initially characterized in brown adipose tissue and actually it is known that this molecule exerts important function in oxidative metabolism, mitochondrial biogenesis and hepatic gluconeogenesis (PUIGSERVER et al., 1998). PGC-1α interacts with diverse hormonal receptors and transcription factors including ERRα, PPARδ, NRF-1, MEF2 with the objective to be recruited by the promoter gene target (SCARPULLA, 2008). In the same way as AMPK, PGC-1α has been associated with the regulation of muscle mass. During muscle atrophy in different conditions the expression of PGC-1alfa decreases (BRAULT et al., 2010; AOI et al., 2010). Any study observed the direct effect of muscle atrophy in the regulation of PGC-1α at physiological level and in normal conditions. The majority of the studies used transgenic animals, existing the possibility that decreased levels of PGC-1α could be a secundary effect and that atrophy were due to physical inactivity. So, there is a protective effect of PGC-1α in inhibit muscle atrophy. Superexpression in vivo of PGC-1 is sufficient to block muscle atrophy, and this mechanism seems to be related to FoxO suppression (SANDRI et al., 2006).


    Beyond its well documented and unique role as mitochondrial biogenesis sensors, AMPK and PGC-1 alfa now emerge as important participants in the regulation of muscle mass. AMPK inhibits mTOR, triggering atrophic stimulus by a mechanism involving TSC2. By other hand, PGC-alfa exerts protective effects in muscle fiber atrophy, by suppressing FoxO. Studies utilizing physiological approaches like physical exercise are necessary to dissect the molecular nature. This concept will allow the development of potential and safe drugs to rescue muscle wasting diseases and improve quality of life.


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