5 research outputs found
Contraction-stimulated glucose transport in muscle is controlled by AMPK and mechanical stress but not sarcoplasmatic reticulum Ca<sup>2+</sup>Â release
Understanding how muscle contraction orchestrates insulin-independent muscle glucose transport may enable development of hyperglycemia-treating drugs. The prevailing concept implicates Ca2+ as a key feed forward regulator of glucose transport with secondary fine-tuning by metabolic feedback signals through proteins such as AMPK. Here, we demonstrate in incubated mouse muscle that Ca2+ release is neither sufficient nor strictly necessary to increase glucose transport. Rather, the glucose transport response is associated with metabolic feedback signals through AMPK, and mechanical stress-activated signals. Furthermore, artificial stimulation of AMPK combined with passive stretch of muscle is additive and sufficient to elicit the full contraction glucose transport response. These results suggest that ATP-turnover and mechanical stress feedback are sufficient to fully increase glucose transport during muscle contraction, and call for a major reconsideration of the established Ca2+ centric paradigm
Regulation of autophagy in human skeletal muscle: effects of exercise, exercise training and insulin stimulation
KEY POINTS: Regulation of autophagy in human muscle in many aspects differs from the majority of previous reports based on studies in cell systems and rodent muscle. An acute bout of exercise and insulin stimulation reduce human muscle autophagosome content. An acute bout of exercise regulates autophagy by a local contractionâinduced mechanism. Exercise training increases the capacity for formation of autophagosomes in human muscle. AMPK activation during exercise seems insufficient to regulate autophagosome content in muscle, while mTORC1 signalling via ULK1 probably mediates the autophagyâinhibiting effect of insulin. ABSTRACT: Studies in rodent muscle suggest that autophagy is regulated by acute exercise, exercise training and insulin stimulation. However, little is known about the regulation of autophagy in human skeletal muscle. Here we investigate the autophagic response to acute oneâlegged exercise, oneâlegged exercise training and subsequent insulin stimulation in exercised and nonâexercised human muscle. Acute oneâlegged exercise decreased (P<0.01) lipidation of microtubuleâassociated protein 1A/1Bâlight chain 3 (LC3) (âź50%) and the LC3âII/LC3âI ratio (âź60%) indicating that content of autophagosomes decreases with exercise in human muscle. The decrease in LC3âII/LC3âI ratio did not correlate with activation of 5â˛AMP activated protein kinase (AMPK) trimer complexes in human muscle. Consistently, pharmacological AMPK activation with 5âaminoimidazoleâ4âcarboxamide riboside (AICAR) in mouse muscle did not affect the LC3âII/LC3âI ratio. Four hours after exercise, insulin further reduced (P<0.01) the LC3âII/LC3âI ratio (âź80%) in muscle of the exercised and nonâexercised leg in humans. This coincided with increased Serâ757 phosphorylation of Unc51 like kinase 1 (ULK1), which is suggested as a mammalian target of rapamycin complex 1 (mTORC1) target. Accordingly, inhibition of mTOR signalling in mouse muscle prevented the ability of insulin to reduce the LC3âII/LC3âI ratio. In response to 3 weeks of oneâlegged exercise training, the LC3âII/LC3âI ratio decreased (P<0.05) in both trained and untrained muscle and this change was largely driven by an increase in LC3âI content. Taken together, acute exercise and insulin stimulation reduce muscle autophagosome content, while exercise training may increase the capacity for formation of autophagosomes in muscle. Moreover, AMPK activation during exercise may not be sufficient to regulate autophagy in muscle, while mTORC1 signalling via ULK1 probably mediates the autophagyâinhibiting effect of insulin