J Physiol 587.21 (2009) p 5005 5005

PERSPECT IVES

Take it to heart: myostatininhibition, mighty mouse andthe quest for a competitive edge

Hector H. ValdiviaDepartment of Physiology, University ofWisconsin, Madison, WI 53711, USA

Email: valdivia@physiology.wisc.edu

Who does not want a sculpted, lean, toned,muscular, strong body? Who wants to suffermuscle wasting, severe weakness, limitedmobility and the plethora of ailmentsassociated with muscular dystrophy? Hardlyanyone, for the quest for a competitive edgein health and the longing for a cure in diseasemay be as old as man’s awareness of beautyand handicap. To keep strong, good-lookingand illness-free (at least through a good partof our life), the human body is endowed withmultiple mechanisms that promote cellulargrowth, repair damaged tissue and favourmolecular turnover to renew life underplacid or strenuous circumstances. Musclegrowth is perhaps the most visible andcomplex of these mechanisms. In it, neuro-trophic factors, hormones, transcriptionalregulators, growth promoters, and countlesscytosolic cofactors converge and interactwith one another to increase the number(hyperplasia) and size (hypertrophia) ofmuscle cells.

Enter myostatin, a member of thetransforming growth factor (TGF)-βsuperfamily of secreted proteins which, bymeans of its dramatic negative influenceon muscle growth and differentiation,appears to be the most devious spoilsportin the muscle-bulging party. Myostatinis a relatively novel player in the musclesignalling field, gaining a firm foot only afterthe discovery that knockout of the MSTNgene, which encodes myostatin, produces‘mighty mice’ (McPherron et al. 1997),and that the rather monstrous-looking,‘double-muscled’ Belgian Blue andPiedmontese cows have defective myo-statin expression (Kambadur et al. 1997).After these observations, several studieshave affirmed the role of myostatin as achalone (endocrine secretion that inhibitsphysiological activity) in skeletal muscle:it is secreted by early-differentiating

myoblasts, suppresses IGF-stimulatedprotein synthesis and directly inhibitsmuscle differentiation, proliferation andgrowth. Thus, the apparent beneficial effecton muscular mass and strength followlogically from inhibition of myostatinfunction. But what is the fate of othermyostatin-secreting organs in these naturaland experimenter-created models?

In a recent issue of The Journal of Physio-logy, Rodgers et al. (2009) systematicallyexplored the effect of myostatin ablationon murine cardiac differentiation, structureand function, and derived some of itsmost important functions in β-adrenergicresponsiveness and in physiological versuspathological hypertrophy. The study iswell justified, as myostatin mRNA wasrobustly detected in cardiac cells, but itsfunction remained unclear. These authorsused a homozygous myostatin knockoutmouse model (MSTN−/−) with ∼30%increase in body weight (due mainly toskeletal muscle gain) and similar increasein cardiac mass. Thus, body weight/heartweight ratio of MSTN−/− mice was nodifferent from wild-type littermates, butthe authors cleverly used biochemical andechocardiographic data to determine thatcardiac hypertrophy is not a compensatorymechanism to hypermuscularity. First,myostatin had a direct effect on isolatedcells, as it inhibited IGF-stimulated andbasal cardiomyoblast differentiation andproliferation, and second, the cardiac hyper-trophy of MSTN−/− mice was eccentric,indicative of physiological hypertrophy, andnot concentric, as typically results fromisometric exercise and from conditionsthat increase after-load. In fact, physio-logical cardiac hypertrophy due to myo-statin ablation was evidenced by normallevels of pathological genetic markers (ANP,BNP,α-actin andβ-MHC), and by increasedcardiac performance. Thus, selective myo-statin inhibition may potentially aidin repairing damaged myocardium byinducing physiological hypertrophy, justas originally proposed for myostatin anti-bodies in the aid of the muscle wastingoccurring in muscular dystrophy.

What mechanisms explain myostatin’sreduction of cardiac performance underbasal and stress conditions? Rodgers et al.(2009) again elegantly measured critical

parameters of excitation–contraction (e-c)coupling and concluded that intracellularCa2+ transients and sarcoplasmic reticulumCa2+ load were increased in MSTN−/−

cardiomyocytes, but myofilament Ca2+

sensitivity was unaltered. Similarly,MSTN−/− cardiomyocytes displayed anaugmented response to isoproterenol,a β-adrenergic agonist, increasing evenfurther Ca2+ mobilization and contractilityand enhancing multiple haemodynamicparameters. Overall, the cardiac effectscharacterized by Rodgers et al. (2009)affirm the notion that myostatin inhibitiongenerates a ‘mighty mouse’ with noapparent deleterious effects, althoughcaution should be exerted because nofunctional analysis of other organs wasconducted, and long-term effects remainunclear. To date, there are no long-termstudies of myostatin inhibition in humans,but Belgian Blue cows appear to havesmaller hearts and a shorter lifespan,whereas whippet MSTN−/− dogs areactually slower than their leaner greyhoundrelatives.

Where do the results of Rodgers et al.(2009) leave us? By clearly showingthat myostatin knockdown enhancescardiac contractility, one could conceiveperformance-enhancing intervention basedon myostatin inhibition, but outstandingquestions remain. Specifically, how doesmyostatin fit in with other known controlsystems of cardiac function? How doesits role relate, for example, to classicalhypertrophic systems like calcineurin,CaMKII and Akt? Why would the bodyhave a system in place to ‘brake’ cardiachypetrophy and development? Couldsuppressing myostatin be bad for the heart,and under what circumstances? Clearly, thejury is still out for myostatin inhibitionas the future in gene doping for desperateathletes.

References

McPherron AC, Lawler AM & Lee SJ (1997).Nature 387, 83–90.

Kambadur R, Sharma M, Smith T & Bass J(1997). Genome Res 7, 910–916.

Rodgers BD, Interlichia JP, Garikipati DK,Mamidi R, Chandra M, Nelson OL, Murry CE& Santana LF (2009). J Physiol 587,4873–4886.

C© 2009 The Author. Journal compilation C© 2009 The Physiological Society DOI: 10.1113/jphysiol.2009.181487