Tax sugar, save muscle?

DEBATES ARE CURRENTLY RAGING in the United States over healthcare reform. Certain political circles are advocating the implementation of a tax on sugary products to reign in ballooning costs associated with treating the one in three individuals in the United States now classified as obese. Now, this is certainly not the appropriate forum to rant over taxes. But, given the ever emerging liability of obesity and related comorbidities to not only quality of life, but financial solvency of individuals and industries, a discussion apropos the latest scientific findings surrounding this epidemic is deserved. The recent paper by Paturi and Blough et al. (9) “Impaired overload-induced hypertrophy in obese Zucker rat slow-twitch skeletal muscle” has suggested a link between obesity and impaired muscle growth attributed to impaired insulin signaling. Desensitization of the insulin receptor (IR) is a hallmark trait of obesity and is a key factor in the development of the now commonly referred to metabolic syndrome—an aggregation of signs that contribute to the onset of coronary artery disease, stroke, and diabetes. Chronic stimulation of the IR, brought about through elevated circulating levels of insulin, amino acids, and/or inflammatory mediators, all signs associated with the metabolic syndrome, promotes for the ultimate demise of IR function. In addition to its role in promoting the uptake and storage of glucose, the IR plays an indispensable role in the promotion of skeletal muscle hypertrophy. The IR, a member of the receptor tyrosine kinase family, promotes for activation of the insulin receptor substrate-1 (IRS-1) through binding growth agonists such as insulin and insulin-like growth factor-1. Most of the messaging transduced through IR/IRS-1 binding is mediated through phosphatidylinositol-3 kinase (PI3K) and downstream to Akt, collectively referred to as the IR/PI3K/Akt signaling axis. Upon activation, Akt phosphorylates and inactivates hamertin (TSC2), a suppressor of the mammalian target of rapamycin complex-1 (mTORC1)—an assembly of proteins including mTOR, raptor, and G protein -subunit-like (G L or LST8), which together drive skeletal muscle hypertrophy. As a result of TSC2 inhibition, mTORC1 activates key downstream molecules, among which includes p70s6k, a ribosomal associated protein that assists in facilitating protein translation initiation. Interestingly, this cell signaling pathway purportedly can regulate itself, in that activation of p70s6k promotes phosphorylation of the IRS-1 on select Ser/Thr residues, which flags the protein for degradation (10). This negative feedback loop is mediated through mTOR, as administration of rapamycin, a known mTOR inhibitor, rescues IRS-1 from phosphorylation and degradation (11). As such, chronic stimulation of the IR/PI3K/Akt signaling axis through chronic elevations in growth agonists results in the ultimate demise of the signaling pathway, leading to not only deficiencies in insulin-stimulated glucose transport, but perhaps impaired skeletal muscle growth. However, the link between IR/PI3K/Akt dysfunction and skeletal muscle hypertrophy as it relates to obesity and related comorbidities is largely unknown. The paper by Paturi and Blough et al. (9) provides evidence that molecular disruption resulting from obesity and insulin resistance indeed blunts skeletal muscle hypertrophy. Unlike wild-type animals in which TSC2 phosphorylation was unchanged with overload, TSC2 phosphorylation was increased nearly threefold with overload in obese Zucker rats. Although corollary in nature, the response in TSC2 mirrored the response in AMPK phosphorylation upon overload in both wild-type and obese Zucker rats. AMPK, a chief metabolic sensor within muscle and known inhibitor of mTOR activity (1), may be playing a strong role in dampening overload-induced hypertrophy associated with insulin resistance and obesity (Fig. 1). AMPK phosphorylation can inhibit mTORC1 function through activation of TSC2 through phosphorylation on alternative Thr/Ser residues (i.e., Thr1227, Ser1345) (4, 7) and through phosphorylation of the mTOR-binding partner raptor (3). Furthermore, AMPK activates FoxO-dependent gene transcription and can potentially regulate FoxO activity through phosphorylation on Akt-independent Ser/Thr sites (2). Activation of