Lack of myostatin impairs mechanical performance and ATP cost of contraction in exercising mouse gastrocnemius muscle in vivo

Abstract

Although it is well established that the lack of myostatin (Mstn) promotes skeletal muscle hypertrophy, the corresponding changes regarding force generation have been studied mainly in vitro and remain conflicting. Furthermore, the metabolic underpinnings of these changes are very poorly documented. To clarify this issue, we have investigated strictly noninvasively in vivo the impact of the lack of Mstn on gastrocnemius muscle function and energetics in Mstn-targeted knockout (Mstn Ϫ/Ϫ ) mice using 1 H-magnetic resonance (MR) imaging and 31 P-MR spectroscopy during maximal repeated isometric contractions induced by transcutaneous electrostimulation. In Mstn Ϫ/Ϫ animals, although body weight, gastrocnemius muscle volume, and absolute force were larger (ϩ38, ϩ118, and ϩ34%, respectively) compared with wild-type (Mstn ϩ/ϩ ) mice, specific force (calculated from MR imaging measurements) was significantly lower (Ϫ36%), and resistance to fatigue was decreased. Besides, Mstn deficiency did not affect phosphorylated compound concentrations and intracellular pH at rest but caused a large increase in ATP cost of contraction (up to ϩ206% compared with Mstn ϩ/ϩ ) throughout the stimulation period. Further, Mstn deficiency limits the shift toward oxidative metabolism during muscle activity despite the fact that oxidative ATP synthesis capacity was not altered. Our data demonstrate in vivo that the absence of Mstn impairs both mechanical performance and energy cost of contraction in hypertrophic muscle. These findings must be kept in mind when considering Mstn as a potential therapeutic target for increasing muscle mass in patients suffering from muscle-wasting disorders. adenosine 5=-triphosphate; skeletal muscle; hypertrophy; energy metabolism; fatigue; nuclear magnetic resonance MYOSTATIN (Mstn) is part of the transforming growth factor-␤ signaling molecule family and acts as an endogenous negative regulator of skeletal muscle growth in mammalians (23). The absence or postnatal blockade of Mstn results in a large and widespread increase in skeletal muscle mass (20,23,24).

Mitochondrial impairment induced by postnatal ActRIIB blockade does not alter function and energy status in exercising mouse glycolytic muscle in vivo

“…Actually, we showed that muscle hypertrophy was not accompanied by a proportional increase in absolute force. On the contrary, specific force was reduced in animals treated with sActRIIB-Fc, in agreement with what has been already reported in hypertrophied muscle of myostatin-deficient mice (2,19,42). Third, we observed that sActRIIB-Fc treatment did not improve maximal tetanic force in vivo.…”

“…One of the major findings of the present study is that long-term disruption of ActRIIB signaling impairs mitochondrial function in skeletal muscle, which is comparable to data obtained in myostatin-deficient animals (2,6,19,45). We found actually that sActRIIB-Fc treatment dramatically reduced the maximal rate of oxidative ATP synthesis (Ϫ42%), which is considered a robust and highly reproducible in vivo index of oxidative mitochondrial capacity and has been widely used in research and clinical applications (4,7,26,32).…”

“…It has been shown that postnatal disruption of ActRIIB signaling in normal mice improves functional parameters such as grip strength (1,33) and absolute force in isolated muscle (1,15) but on the other hand decreases resistance to fatigue (15,52). These results are in all respects comparable to those obtained in myostatin-deficient mice in which improved force has been documented (2,19,43,45) and the increased fatigability has been assigned to a mitochondrial impairment evidenced on the basis of in vitro assays (45,48) and in vivo 31 P-MRS measurements (6,19). Interestingly, long-term sActRIIB-Fc treatment in wild-type mice has been shown to reduce the expression of oxidative phosphorylation genes (50,52,60) as well as the level of porin, an outer mitochondrial membrane protein involved in ATP transport between the cytosol and the mitochondrial matrix (52).…”

“…The rate of proton efflux from the muscle (in mM/min) was calculated in the early stage of the postexercise recovery period from the changes in pH and levels of high-energy phosphorylated contents, as described previously (19,28). PCr cost of contraction (PCrcost, in mol/Ns) was calculated as the ratio between VPCrstim and the specific force generated at the start of the fatiguing exercise.…”

Myostatin deficiency is associated with lipidomic abnormalities in skeletal muscles

“…Indeed, beyond muscle hypertrophy, Mstn KO mice show a disturbed muscle function with loss of muscle strength and endurance in vivo or ex vivo accompanied with a decrease in mechanical performance, and ATP production during exercise [11,12,13,14]. In parallel, many other metabolic changes have been documented in Mstn KO muscle such as a decrease in mitochondrial content, disturbance in mitochondrial respiratory function with a decay in the respiratory control ratio in intermyofibrillar mitochondria, and a decline in porine activity [11,13,15].…”