Author: Vekaria, Hemendra ; Sullivan, Patrick ; Joshi, Smita ; Whiteheart, Sidney W ; Lykins, Joshua ; Prakhya, Kanakanagavalli Shravani ; Coenen, Daniёlle M ; Omali, Linda ; Wang, Qing Jun ; Alfar, Hammodah R

Although the presence of glycogen in platelets was established in the 1960s, its importance to specific functions (i.e., activation, secretion, aggregation, and clot contraction) remains unclear. Patients with glycogen storage disease often present with increased bleeding and glycogen phosphorylase (GP) inhibitors, when used as treatments for diabetes, induce bleeding in preclinical studies suggesting some role for this form of glucose in hemostasis. In the present work, we examined how glycogen mobilization affects platelet function using GP inhibitors (CP316819 and CP91149) and a battery of ex vivo assays. Blocking GP activity increased glycogen levels in resting and thrombin-activated platelets and inhibited platelet secretion and clot contraction, with minimal effects on aggregation. Seahorse energy flux analysis and metabolite supplementation experiments suggested that glycogen is an important metabolic fuel whose role is affected by platelet activation and the availability of external glucose and other metabolic fuels. Our data shed light on the bleeding diathesis in glycogen storage disease patients and offer insights into the potential effects of hyperglycemia on platelets.

01 Jul 2020·The Journal of PhysiologyQ2 · MEDICINE

Contraction‐regulated mTORC1 and protein synthesis: Influence of AMPK and glycogen

Q2 · MEDICINE

Article

Author: Li, Zhencheng ; Jensen, Thomas E. ; Persson, Kaspar W. ; Knudsen, Jonas R. ; Li, Jingwen ; Henriquez‐Olguin, Carlos

Key points

AMP‐activated protein kinase (AMPK)‐dependent Raptor Ser792 phosphorylation does not influence mechanistic target of rapamycin complex 1 (mTORC1)‐S6K1 activation by intense muscle contraction.

α2‐AMPK activity‐deficient mice have lower contraction‐stimulated protein synthesis.

Increasing glycogen activates mTORC1‐S6K1.

Normalizing muscle glycogen content rescues reduced protein synthesis in AMPK‐deficient mice.

AbstractThe mechansitic target of rapamycin complex 1 (mTORC1)‐S6K1 signalling pathway regulates muscle growth‐related protein synthesis and is antagonized by AMP‐activated protein kinase (AMPK) in multiple cell types. Resistance exercise stimulates skeletal muscle mTORC1‐S6K1 and AMPK signalling and post‐contraction protein synthesis. Glycogen inhibits AMPK and has been proposed as a pro‐anabolic stimulus. The present study aimed to investigate how muscle mTORC1‐S6K1 signalling and protein synthesis respond to resistance exercise‐mimicking contraction in the absence of AMPK and with glycogen manipulation. Resistance exercise‐mimicking unilateral in situ contraction of musculus quadriceps femoris in anaesthetized wild‐type and dominant negative α2 AMPK kinase dead transgenic (KD‐AMPK) mice, measuring muscle mTORC1 and AMPK signalling immediately (0 h) and 4 h post‐contraction, and protein‐synthesis at 4 h. Muscle glycogen manipulation by 5 day oral gavage of the glycogen phosphorylase inhibitor CP316819 and sucrose (80 g L−1) in the drinking water prior to in situ contraction. The mTORC1‐S6K1 and AMPK signalling axes were coactivated immediately post‐contraction, despite potent AMPK‐dependent Ser792 phosphorylation on the mTORC1 subunit raptor. KD‐AMPK muscles displayed normal mTORC1‐S6K1 activation at 0 h and 4 h post‐exercise, although there was impaired contraction‐stimulated protein synthesis 4 h post‐contraction. Pharmacological/dietary elevation of muscle glycogen content augmented contraction‐stimulated mTORC1‐S6K1‐S6 signalling and rescued the reduced protein synthesis‐response in KD‐AMPK to wild‐type levels. mTORC‐S6K1 signalling is not influenced by α2‐AMPK during or after intense muscle contraction. Elevated glycogen augments mTORC1‐S6K1 signalling. α2‐AMPK‐deficient KD‐AMPK mice display impaired contraction‐induced muscle protein synthesis, which can be rescued by normalizing muscle glycogen content.

01 Feb 2020·The Journal of PhysiologyQ2 · MEDICINE

Inhibition of glycogenolysis prolongs action potential repriming period and impairs muscle function in rat skeletal muscle

Q2 · MEDICINE

Article

Author: Nielsen, Joachim ; Ørtenblad, Niels ; Jensen, Rasmus

Key points

Muscle glycogen content is associated with muscle function, but the physiological link between the two is poorly understood.

This study investigated the effects of inhibiting glycogenolysis, while maintaining high overall energy status, on different aspects of muscle function.

We demonstrate here that Na+,K+‐ATPase activity depends on glycogenolytically derived ATP regardless of high global ATP, with a decrease in activity leading to reduced force production and accelerated fatigue development.

The results support the concept of compartmentalized energy transfer with glycogen metabolism playing a crucial role in intramuscular ATP resynthesis and ion regulation.

This study gives specific insights into muscular function and may help towards a better understanding of glycogen storage diseases and muscle fatigue.

AbstractSkeletal muscle glycogen content is associated with muscle function and fatigability. However, little is known about the physiological link between glycogen content and muscle function. Here we aimed to investigate the importance of glycogenolytically derived ATP per se on muscle force and action potential (AP) repriming period, i.e. the time before a second AP can be produced (indicative of Na+,K+‐ATPase activity). Single fibres from rat extensor digitorum longus muscles were isolated and mechanically skinned in order to investigate force production and the AP repriming period while global ATP and PCr concentrations were kept high. The importance of glycogenolytically derived ATP was studied by inhibition of glycogen phosphorylase (1,4‐dideoxy‐1,4‐imino‐d‐arabinitol (DAB; 2 mm) or CP‐316,819 (CP; 10 µm)) or glycogen removal (amyloglucosidase, 20 U ml−1). Tetanic force decreased by (mean (SD)) 21 (15)% (P < 0.001) and 76 (28)% (DAB) or 94 (6)% (CP, P < 0.001) in well‐polarized and partially depolarized fibres, respectively. In depolarized fibres, twitch force decreased by 16 (10)% and 55 (26)% with DAB and CP, respectively, with no effect in well‐polarized fibres (84 (10)%, P = 0.14). There was no effect of glycogen phosphorylase inhibition on repriming period in well‐polarized fibres (median (25th, 75th percentile): 5 (4, 5) vs. 4 (4, 5) ms, P = 0.26), while the repriming period was prolonged from 6 (5, 7) to 8 (7, 10) ms (P = 0.01) in partially depolarized fibres. In line with this, glycogen removal increased repriming period from 5 (5, 6) to 6 (5, 7) ms (P = 0.003) in depolarized fibres. Together, these data strongly indicate that blocking glycogenolysis attenuates Na+,K+‐ATPase activity, which in turn increases the repriming period and reduces force, demonstrating a functional link between glycogenolytically derived ATP and force production.

100 Deals associated with CP-316819

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 1	-	Pfizer Inc.	-

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