Combined Strategies for Maintaining Skeletal Muscle Mass and Function in Aging: Myostatin Inactivation and AICAR-Associated Oxidative Metabolism Induction

Abstract

Myostatin (mstn) blockade, resulting in muscle hypertrophy, is a promising therapy to counteract age-related muscle loss. However, oxidative and mitochondrial deficit observed in young mice with myostatin inhibition could be detrimental with aging. The aim of this study was (a) to bring original data on metabolic and mitochondrial consequences of mstn inhibition in old mice, and (b) to examine whether 4-weeks of AICAR treatment, a pharmacological compound known to upregulate oxidative metabolism, may be useful to improve exercise capacity and mitochondrial deficit of 20-months mstn KO versus wild-type (WT) mice. Our results show that despite the enlarged muscle mass, the oxidative and mitochondrial deficit associated with reduced endurance running capacity is maintained in old mstn KO mice but not worsened by aging. Importantly, AICAR treatment induced a significant beneficial effect on running limit time only in old mstn KO mice, with a marked increase in PGC-1α expression and slight beneficial effects on mitochondrial function. We showed that AICAR effects were autophagy-independent. This study underlines the relevance of aged muscle remodelling by complementary approaches that impact both muscle mass and function, and suggest that mstn inhibition and aerobic metabolism activators should be co-developed for delaying age-related deficits in skeletal muscle.

Myostatin deficiency is associated with lipidomic abnormalities in skeletal muscles

“…In addition, we demonstrated that the levels of cytosolic (FABP3) and sarcolemmal lipid transporters (FATP1, FATP4) are reduced, in agreement with our previous observation showing a significant reduction of FAT/CD36 levels [16]. It should be noted that CD36, FABP3, FATP1 and FATP4 are co-expressed in skeletal muscle, and all of these proteins contributed to transport, with recent evidence suggesting that CD36 and FATP4 are qualitatively the most important [53].…”

“…Here, we showed that Mstn gene deletion results in reduced lipolytic machinery in Mstn deficient hypertrophic muscles (impaired mitochondrial yield, CS and β-HAD activities and Cpt1 and Ppar- gene expressions), in line with previous studies showing that oxidative metabolism is diminished in several models of Mstn deficiency [12,13,15,16,51]. In addition, we demonstrated that the levels of cytosolic (FABP3) and sarcolemmal lipid transporters (FATP1, FATP4) are reduced, in agreement with our previous observation showing a significant reduction of FAT/CD36 levels [16].…”

“…In the same vein, Relizani et al reported that the blockade of mstn decreased mRNA levels of Pdk4, a regulatory protein switch of substrate utilization from glucose towards fatty acids [15]. In a previous study, we observed in aged Mstn KO EDL muscle a significant increase in GLUT4 protein levels, and a decrease in FAT/CD36 protein levels compared to aged WT mice [16]. In the present study, we confirm the increased content of muscle glucose uptake markers in mstn KO muscle.…”

“…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]. In addition, a decrease of fatty acid translocase (FAT/CD36) level, a lipid transporter, and the citrate synthase (CS) activity, one of the main mitochondrial oxidative enzyme, associated with a lower peroxisome proliferatoractivated receptor gamma coactivator 1 alpha (PGC1-α) expression has been observed [15,16].…”

Schisandrae fructus enhances myogenic differentiation and inhibits atrophy through protein synthesis in human myotubes

“…[1][2][3][4][5] Search for the dietary supplements to ameliorate and maintain skeletal muscle function is becoming an important topic in antiaging research field. [49][50][51][52][53][54][55] Muscle growth starts by the activation of quiescent myoblasts (proliferation). These cells get committed to myogenic differentiation and fuse with existing muscle fibers.…”