IGF is an anabolic growth factor

IGF1 is an anabolic growth factor that induces hypertrophy and blocks atrophy in skeletal muscle by activating the PI3K/AKT/mTOR pathway (Egerman and Glass, 2014). In addition to its anabolic and anti-catabolic effects, IGF1 stimulates fatty 1186 (FA) uptake and glucose metabolism (Clemmons, 2012). Whereas both FAs and glucose can be used to generate ATP, glucose can also support de novo lipid synthesis via cytosolic citrate metabolism (Vander Heiden et al., 2009), which is an important step to meet the demand of membrane expansion during skeletal muscle growth. Cardiolipin is a phospholipid specific to the inner mitochondrial membrane, where it plays an important role in structural organization and function of these membranes (Paradies et al., 2014, Ren et al., 2014). ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the conversion of mitochondria-derived citrate into oxaloacetate and acetyl-CoA, which are further utilized as building blocks for lipid synthesis and acetylation. Acetyl-CoA is vital for acetylation reactions that modify proteins including histones, affecting their functions (Lee et al., 2014, Wellen et al., 2009). In the current study, we investigated the role of ACL in regulating lipid metabolism and mitochondrial function in skeletal muscle and whether metabolic effects orchestrated by IGF1 are regulated by ACL.
Results
Discussion ACL has been appreciated for its role in fatty acid (FA) biosynthesis and its requirement in the production of acetyl-CoA (Wellen et al., 2009, Choudhary et al., 2014). However, ACL’s role in other metabolic processes, particularly in skeletal muscle, has not been extensively studied. Recently, Lee et al. reported that AKT phosphorylates and increases the activity of ACL via a PI3K-dependent pathway in cancer cells (Lee et al., 2014). This finding gave context to our observation that IGF1 was capable of increasing phospho-ACL levels and de novo lipid synthesis in skeletal muscle in an ACL-dependent manner. Further exploration demonstrated that ACL was capable of increasing levels of cardiolipin, a critical component of the mitochondrial membrane that constitutes about 20% of the organelle’s FA composition (Paradies et al., 2014, Ren et al., 2014), opening up a new arena for ACL-required biology. ACL was found to be required for maintenance of cardiolipin, which in turn modulated mitochondrial complex formation. ACL activity is thus limiting for this critical process—critical because complex formation modulates ATP levels. It was previously demonstrated that IGF1 is an anabolic agent for skeletal muscle; it induces protein synthesis via the AKT/mTOR pathway and blocks protein breakdown by inhibiting FOXO induction of the E3 ligases MuRF1 and MAFbx, which mediate muscle protein degradation (Egerman and Glass, 2014). What hadn’t been understood previously was that IGF1 could also perturb mitochondrial metabolism, as shown in this study. It seems especially noteworthy that a growth factor that induces protein synthesis is also able to induce the required ATP necessary for the production of new proteins, as well as to facilitate correct protein folding and subsequent protein function. In contrast, in many settings mitochondrial stimulation has seemed to be at odds with anabolic protein synthesis. For example, PGC1α, a transcriptional co-activator that stimulates mitochondriogenesis, is itself induced by AMPK activation (Lee et al., 2006), which at the same time actually inhibits mTOR signaling. Also, anabolic stimuli by mechanisms such as myostatin inhibition can induce hypertrophy without increasing mitochondrial function, and this sort of effect in part might explain why some anabolic stimuli result in more fatigable muscle (LeBrasseur et al., 2009, Mouisel et al., 2014). However, this study gives at least one physiologic mechanism in which both anabolic stimuli and mitochondria might be stimulated—not by increasing mitochondrial number, but by increasing mitochondrial efficiency.