A DGKζ-FoxO-ubiquitin proteolytic axis controls fiber size during skeletal muscle remodeling

Abstract

Skeletal muscle rapidly remodels in response to various stresses, and the resulting changes in muscle mass profoundly influence our health and quality of life. We identified a diacylglycerol kinase ζ (DGKζ)–mediated pathway that regulated muscle mass during remodeling. During mechanical overload, DGKζ abundance was increased and required for effective hypertrophy. DGKζ not only augmented anabolic responses but also suppressed ubiquitin-proteasome system (UPS)–dependent proteolysis. We found that DGKζ inhibited the transcription factor FoxO that promotes the induction of the UPS. This function was mediated through a mechanism that was independent of kinase activity but dependent on the nuclear localization of DGKζ. During denervation, DGKζ abundance was also increased and was required for mitigating the activation of FoxO-UPS and the induction of atrophy. Conversely, overexpression of DGKζ prevented fasting-induced atrophy. Therefore, DGKζ is an inhibitor of the FoxO-UPS pathway, and interventions that increase its abundance could prevent muscle wasting.

The role of raptor in the mechanical load‐induced regulation of mTOR signaling, protein synthesis, and skeletal muscle hypertrophy

“…Alterations in skeletal muscle mass are driven by changes in the balance between the rate of protein synthesis and protein degradation, and signaling by mTOR has been widely implicated in the regulation of protein synthesis (34)(35)(36). Consistent with this notion, several studies have shown that rapamycin can prevent the initial increase in protein synthesis that occurs in response to various forms of mechanical stimulation (9,(37)(38)(39).…”

Recent advances in understanding resistance exercise training-induced skeletal muscle hypertrophy in humans

“…The protein encoded by NAP1L1 controls chromatin compaction but has also been shown to bind to and regulate the nuclear-cytoplasmic shuttling of DGKζ 68 . Importantly, DGKζ was shown recently to play a pivotal role in mechanical overload-induced muscle hypertrophy in rodents, but only if the nuclear localization signal of DGKζ was intact 69 . While the nature of this interaction in humans warrants further investigation, the example attests to the hypothesis-generating power of transcriptome profiling and its inherent potential for biological discovery.…”

Negative control of diacylglycerol kinase ζ‐mediated inhibition of T cell receptor signaling by nuclear sequestration in mice

“…Subcellular localization of DGKζ varies dramatically among different cell types. It has been shown to localize predominantly in the nucleus, in the cytosolic compartment, or distribute in both nucleus and cytosol dependent on different cell types and tissues examined [41,44,47,74‐77]. Our data indicate that DGKζ function is dynamically regulated in T cells via shuttling between the cytosol and nucleus and that nuclear localization of DGKζ serves as a negative control of DGKζ function by preventing it from accessing its substrate in the cytoplasmic membrane.…”

“…The nucleus contains different pools of DAG and nuclear DGKζ has been shown to reduce nuclear DAG concentration in HEK293 cells [44]. In the nucleus of skeletal muscle, nuclear DGKζ interacts with the class O of forkhead box transcription factor (FoxO) to mitigate FoxO‐mediated ubiquitin‐proteasome system dependent proteolysis to prevent muscle atrophy, which is independent on its kinase activity but dependent on its nuclear localization [77]. Whether nuclear DGKζ performs similar functions in T cells remains to be determined.…”