Examinando por Autor "Roland Knudsen, Jonas"

Mostrando 1 - 2 de 2
  • Miniatura
    Ítem
    Activin receptor type IIA/IIB blockade increases muscle mass and strength, but compromises glycemic control in mice
    (Elsevier, 2025-09-27) Carlsson, Michala; Ali, Mona Sadek; Frank, Emma; Mármol, Joan M.; Ali, Mona Sadek; Raun, Steffen H.; Battey, Edmund; Resen Andersen, Nicoline; Irazoki, Andrea; Lund, Camilla; Henríquez-Olguín, Carlos; Kubec Højfeldt, Martina; Blomquist, Pauline; Duch Bromer, Frederik; Mocciaro, Gabriele; Lodberg, AndreasBrix Folsted Andersen, Christian; Eijken, Marco; Mæchel Fritzen, Andreas; Roland Knudsen, Jonas; Richter, Erik A.; Sylow, Lykke
    Purpose: Blocking the Activin receptor type IIA and IIB (ActRIIA/IIB) has clinical potential to increase muscle mass and improve glycemic control in obesity, cancer, and aging. However, the impact of blocking ActRIIA/IIB on strength, metabolic regulation, and insulin action remains unclear. Methods: Here, we investigated the effect of short- (10 mg kg− 1 bw, once, 40h) or long-term (10 mg kg− 1 bw, twice weekly, 21 days) antibody treatment targeting ActRIIA/IIB αActRIIA/IIB) in lean and diet-induced obese mice and engineered human muscle tissue. Results: Short-term α ActRIIA/IIB administration in lean mice increased insulin-stimulated glucose uptake in skeletal muscle by 76—105%. Despite this, αActRIIA/IIB-treated mice exhibited 33% elevated blood glucose and glucose intolerance. Long-term αActRIIA/IIB treatment increased muscle mass (+20%) and reduced fat mass (− 8%) in obese mice but failed to enhance insulin-stimulated glucose uptake in muscle or adipose tissue. Instead, it induced glucose intolerance, cardiac hypertrophy with glycogen accumulation, and elevated hepatic triacylglycerol and glucose output in response to pyruvate. Concomitantly, long-term αActRIIA/IIB treatment increased strength (+30%) in mouse soleus muscle and prevented activin A-induced loss of tissue strength in engineered human muscle tissue. Surprisingly, long-term α ActRIIA/IIB treatment lowered volitional running (− 250%). Conclusions: Our findings demonstrate that, in accordance with human studies, ActRIIA/IIB blockade holds promise for increasing muscle mass, strength, and muscle insulin sensitivity. However, contrary to the improved glycemic control in humans, ActRIIA/IIB blockade in mice causes severe glucose intolerance and lowers voluntary physical activity. Our study underscores the complex metabolic and functional consequences of ActRIIA/IIB blockade, and highlight species differences on glycemic control, which warrant further investigation.
  • Miniatura
    Ítem
    Skeletal muscle Rac1 mediates exercise training adaptations towards muscle glycogen resynthesis and protein synthesis
    (Elsevier, 2025-08-28) Raun, Steffen H.; Henriquez-Olguín, Carlos; Frank, Emma; Schlabs, Farina; Hahn, Nanna Just; Roland Knudsen, Jonas; Ali, Mona S.; Andersen, Nicoline R.; Møller, Lisbeth L.V.; Davey, Jonathan; Qian, Hongwei; Coelho, Ana; Carl, Christian S.; Voldstedlund, Christian T.; Kiens, Bente; Holmdahl, Rikard; Gregorevic, Paul; Jensen, Thomas E.; Deshmukh, Atul S.; Richter, Erik A.; Sylow, Lykke
    Long-term exercise training elicits tremendous health benefits; however, the molecular understanding is incomplete and identifying therapeutic targets has been challenging. Rho GTPases are among the most regulated groups of proteins after exercise in human skeletal muscle, yet, unexplored candidates for mediating the effects of exercise training. We found that the Rho GTPase Rac1 was activated acutely after multiple exercise modalities in human skeletal muscle. Loss of Rac1 specifically in muscle attenuated contraction-induced muscle protein synthesis, diminished improvements in running capacity, and prevented muscle hypertrophy after exercise training in mice. Additionally, Ncf1* mice revealed that Rac1 regulated glycogen resynthesis via a NOX2-dependent mechanism. Molecularly, Rac1 was required for contraction-induced p38MAPK signaling towards HSP27, MNK1, and CREB phosphorylation. In vivo muscle-targeted overexpression of a hyperactive Rac1-mutant elevated reactive oxidant species production during exercise but did not affect muscle mass. Using mass spectrometry-based proteomics, we found that loss or gain of Rac1 muscle protein affected pathways related to cytoskeleton organization, muscle adaptation, and large ribosomal subunits. Thus, skeletal muscle Rac1 mediates both molecular and functional adaptation to exercise training.