A Prevalent Variant in PPP1R3A Impairs Glycogen Synthesis and Reduces Muscle Glycogen Content in Humans and Mice

Abstract

BackgroundStored glycogen is an important source of energy for skeletal muscle. Human genetic disorders primarily affecting skeletal muscle glycogen turnover are well-recognised, but rare. We previously reported that a frameshift/premature stop mutation in PPP1R3A, the gene encoding RGL, a key regulator of muscle glycogen metabolism, was present in 1.36% of participants from a population of white individuals in the UK. However, the functional implications of the mutation were not known. The objective of this study was to characterise the molecular and physiological consequences of this genetic variant.Methods and FindingsIn this study we found a similar prevalence of the variant in an independent UK white population of 744 participants (1.46%) and, using in vivo 13C magnetic resonance spectroscopy studies, demonstrate that human carriers (n = 6) of the variant have low basal (65% lower, p = 0.002) and postprandial muscle glycogen levels. Mice engineered to express the equivalent mutation had similarly decreased muscle glycogen levels (40% lower in heterozygous knock-in mice, p < 0.05). In muscle tissue from these mice, failure of the truncated mutant to bind glycogen and colocalize with glycogen synthase (GS) decreased GS and increased glycogen phosphorylase activity states, which account for the decreased glycogen content.ConclusionsThus, PPP1R3A C1984ΔAG (stop codon 668) is, to our knowledge, the first prevalent mutation described that directly impairs glycogen synthesis and decreases glycogen levels in human skeletal muscle. The fact that it is present in ∼1 in 70 UK whites increases the potential biomedical relevance of these observations.

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

“…These mice demonstrated impaired glycogen synthesis associated with the inactivation of glycogen synthase (i.e. hyperphosphorylation), thus phenocopying the GM-null mice ( Table 3) [102]. This result suggests that a disturbance of the binding of a gPIP to its subcellular structure can lead to a nonfunctional PP1 holoenzyme.…”

Glycogen and its metabolism: some new developments and old themes

“…However, in these mice, the phosphorylation of both glycogen synthase and phosphorylase was modified. In humans, a common nonsense mutation in the PPP1R3A gene, which encodes R GL , was identified in 1.4% of the white population in the U.K. [154]. The mutation resulted in a truncated R GL protein and a decrease in muscle glycogen accumulation.…”

Type 2 Diabetes

“…Mice totally lacking in skeletal muscle insulin receptors do not develop diabetes (27). Humans who have the PPP1R3A genetic variant of muscle glycogen synthase cannot store glycogen in muscle after meals but are not necessarily hyperglycemic (28). Many normoglycemic individuals maintain normal blood glucose levels with a degree of muscle insulin resistance identical to those with type 2 diabetes (29).…”