Muscle Glycogen Phosphorylase and Its Functional Partners in Health and Disease

Abstract

Glycogen phosphorylase (PG) is a key enzyme taking part in the first step of glycogenolysis. Muscle glycogen phosphorylase (PYGM) differs from other PG isoforms in expression pattern and biochemical properties. The main role of PYGM is providing sufficient energy for muscle contraction. However, it is expressed in tissues other than muscle, such as the brain, lymphoid tissues, and blood. PYGM is important not only in glycogen metabolism, but also in such diverse processes as the insulin and glucagon signaling pathway, insulin resistance, necroptosis, immune response, and phototransduction. PYGM is implicated in several pathological states, such as muscle glycogen phosphorylase deficiency (McArdle disease), schizophrenia, and cancer. Here we attempt to analyze the available data regarding the protein partners of PYGM to shed light on its possible interactions and functions. We also underline the potential for zebrafish to become a convenient and applicable model to study PYGM functions, especially because of its unique features that can complement data obtained from other approaches.

Preclinical Research in McArdle Disease: A Review of Research Models and Therapeutic Strategies

“…The zebrafish model of the disease offers some advantages with respect the bovine, ovine and mouse models, such as production of a large number of embryos, short life cycle (at least vs. the bovine and ovine model, with maturity reached within 3 months) and less expensive maintenance [ 6 , 45 ] ( Table 1 ). In addition, the glycogen concentrations reported for this model (1.3 times higher than in controls) are relatively similar to the actual findings in humans, as opposed to the mouse model.…”

“…A zebrafish model of McArdle disease has been recently reported [ 6 , 45 ] ( Table 1 ). The zebrafish ( Danio rerio ) has two genes encoding GP-MM: phosphorylase, glycogen muscle, A ( Pygma ) and B ( Pygmb ) genes, respectively (with both sharing more than 80% of sequence identity with human PYGM gene).…”

“…When Pygma and Pygmb genes were knocked down by injecting translation-blocking morpholino oligonucleotides, GP-MM protein levels were reduced in zebrafish morphants, which exhibited a curved body, reduced length, deformations in the tail region and pericardial edema. Additionally, they also showed decreased skeletal muscle formation, disintegrated muscle structure, loss of myofiber organization and accumulation of glycogen granules between sarcomeres and in the subsarcolemmal region, accompanied by a reduction of mobility and swimming speed [ 6 , 45 ].…”

“…McArdle disease is caused by inherited deficiency of myophosphorylase, the skeletal muscle-specific isoform of glycogen phosphorylase (GP-MM), with preservation of the other two glycogen phosphorylase isoforms, the liver (GP-LL) and brain glycogen phosphorylase (GP-BB); as such, this defect essentially leads to myopathy with no alterations of glycogen metabolism reported in other tissues [ 4 ]. However, the fact that GP-MM expression has been detected not only in skeletal muscle—or in organs containing skeletal muscle tissue such as the tongue, glands and esophagus—but also in different parts of the brain (e.g., cerebellum), lymphoid tissues, lymphocytes, granulocytes, retina, kidney, male reproductive organs or adipose tissue [ 5 , 6 , 7 , 8 , 9 ], deserves attention and should be the subject of further studies.…”

Czego jeszcze nie wiemy o mięśniach szkieletowych?

“…"PYGM" ma znaczenie w tak różnorodnych procesach, jak szlaki sygnałowe insuliny i glukagonu, insulinooporność, nekroptoza, odpowiedź immunologiczna i fototransdukcja. Oprócz choroby McArdle'a "PYGM" jest także istotny w innych procesach patologicznych, takich jak schizofrenia czy nowotwór [73].…”