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2016 ; 594
(3
): 745-61
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Regulation of autophagy in human skeletal muscle: effects of exercise, exercise
training and insulin stimulation
#MMPMID26614120
Fritzen AM
; Madsen AB
; Kleinert M
; Treebak JT
; Lundsgaard AM
; Jensen TE
; Richter EA
; Wojtaszewski J
; Kiens B
; Frøsig C
J Physiol
2016[Feb]; 594
(3
): 745-61
PMID26614120
show ga
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
contraction-induced 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 autophagy-inhibiting effect of insulin.
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 one-legged exercise, one-legged exercise training
and subsequent insulin stimulation in exercised and non-exercised human muscle.
Acute one-legged exercise decreased (P<0.01) lipidation of microtubule-associated
protein 1A/1B-light chain 3 (LC3) (? 50%) and the LC3-II/LC3-I ratio (? 60%)
indicating that content of autophagosomes decreases with exercise in human
muscle. The decrease in LC3-II/LC3-I ratio did not correlate with activation of
5'AMP activated protein kinase (AMPK) trimer complexes in human muscle.
Consistently, pharmacological AMPK activation with 5-aminoimidazole-4-carboxamide
riboside (AICAR) in mouse muscle did not affect the LC3-II/LC3-I ratio. Four
hours after exercise, insulin further reduced (P<0.01) the LC3-II/LC3-I ratio (?
80%) in muscle of the exercised and non-exercised leg in humans. This coincided
with increased Ser-757 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 LC3-II/LC3-I ratio. In response to 3 weeks of one-legged
exercise training, the LC3-II/LC3-I ratio decreased (P<0.05) in both trained and
untrained muscle and this change was largely driven by an increase in LC3-I
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 autophagy-inhibiting effect of insulin.