Combined aerobic exercise and enzyme replacement therapy rejuvenates the mitochondrial–lysosomal axis and alleviates autophagic blockage in Pompe disease

Nilsson, Mats I.; MacNeil, Lauren; Kitaoka, Yu; Suri, Rahul; Young, Sarah P.; Kaczor, Jan Jacek; Nates, N.J.; Ansari, M.U.; Wong, Tatianna Wai Ying; Ahktar, Most. Afia; Brandt, Linda; Hettinga, Bart P.; Tarnopolsky, Mark A.

doi:10.1016/j.freeradbiomed.2015.05.019

Cited by 28 publications

(23 citation statements)

References 94 publications

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“…Changes in the levels of p62 are often used as a surrogate marker of autophagy flux, because p62 is degraded via the autophagy pathway. Other studies have found that p62 levels in muscle are either not changed (Greene et al 2015;McMillan et al 2015;Nilsson et al 2015), downregulated (Lira et al 2013), or increased (Fritzen et al 2016) in response to endurance exercise training. These differential results in p62 may be attributable to the use of various exercise protocols (chronic vs. intermittent muscle activity), species, muscle fiber types, or the time of sampling during the adaptive process (Lira et al 2013).…”

Section: Discussionmentioning

confidence: 93%

Regulation of the autophagy system during chronic contractile activity-induced muscle adaptations

Kim

Hood

2017

Physiol Rep

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Skeletal muscle is adaptable to exercise stimuli via the upregulation of mitochondrial biogenesis, and recent studies have suggested that autophagy also plays a role in exercise‐induced muscle adaptations. However, it is still obscure how muscle regulates autophagy over the time course of training adaptations. This study examined the expression of autophagic proteins in skeletal muscle of rats exposed to chronic contractile activity (CCA; 6 h/day, 9V, 10 Hz continuous, 0.1 msec pulse duration) for 1, 3, and 7 days (n = 8/group). CCA‐induced mitochondrial adaptations were observed by day 7, as shown by the increase in mitochondrial proteins (PGC‐1α, COX I, and COX IV), as well as COX activity. Notably, the ratio of LC3 II/LC3 I, an indicator of autophagy, decreased by day 7 largely due to a significant increase in LC3 I. The autophagic induction marker p62 was elevated on day 3 and returned to basal levels by day 7, suggesting a time‐dependent increase in autophagic flux. The lysosomal system was upregulated early, prior to changes in mitochondrial proteins, as represented by increases in lysosomal system markers LAMP1, LAMP2A, and MCOLN1 as early as by day 1, as well as TFEB, a primary regulator of lysosomal biogenesis and autophagy flux. Our findings suggest that, in response to chronic exercise, autophagy is upregulated concomitant with mitochondrial adaptations. Notably, our data reveal the surprising adaptive plasticity of the lysosome in response to chronic contractile activity which enhances muscle health by providing cells with a greater capacity for macromolecular and organelle turnover.

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Section: Discussionmentioning

confidence: 93%

Regulation of the autophagy system during chronic contractile activity-induced muscle adaptations

Kim

Hood

2017

Physiol Rep

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“…Fresh plantaris tissue was immediately fixed in 2% (v/v) glutaraldehyde in 0.1 mol/L sodium cacodylate buffer and processed as described previously . Eight representative micrographs from a unique fibre containing a portion of the subsarcolemmal region adjacent to the nucleus with most of the image containing the intermyofibrillar area were acquired at ×15 000 magnification.…”

Section: Methodsmentioning

confidence: 99%

“…45,46 Transmission electron microscopy Fresh plantaris tissue was immediately fixed in 2% (v/v) glutaraldehyde in 0.1 mol/L sodium cacodylate buffer and processed as described previously. 47 Eight representative micrographs from a unique fibre containing a portion of the subsarcolemmal region adjacent to the nucleus with most of the image containing the intermyofibrillar area were acquired at ×15 000 magnification. Quantification was achieved using the Nikon Elements software by manually outlining mitochondria and converting these to actual size using a calibration grid.…”

Section: In Vitro Muscle and Blood Analysesmentioning

confidence: 99%

Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H₂O₂ emission during impaired oxidative phosphorylation

Hughes

Turnbull

Rebalka

et al. 2019

J cachexia sarcopenia muscle

126

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Background Muscle wasting and weakness in Duchenne muscular dystrophy (DMD) causes severe locomotor limitations and early death due in part to respiratory muscle failure. Given that current clinical practice focuses on treating secondary complications in this genetic disease, there is a clear need to identify additional contributions in the aetiology of this myopathy for knowledge‐guided therapy development. Here, we address the unresolved question of whether the complex impairments observed in DMD are linked to elevated mitochondrial H 2 O 2 emission in conjunction with impaired oxidative phosphorylation. This study performed a systematic evaluation of the nature and degree of mitochondrial‐derived H 2 O 2 emission and mitochondrial oxidative dysfunction in a mouse model of DMD by designing in vitro bioenergetic assessments that attempt to mimic in vivo conditions known to be critical for the regulation of mitochondrial bioenergetics. Methods Mitochondrial bioenergetics were compared with functional and histopathological indices of myopathy early in DMD (4 weeks) in D2.B10‐DMD mdx /2J mice (D2. mdx )—a model that demonstrates severe muscle weakness. Adenosine diphosphate's (ADP's) central effect of attenuating H 2 O 2 emission while stimulating respiration was compared under two models of mitochondrial‐cytoplasmic phosphate exchange (creatine independent and dependent) in muscles that stained positive for membrane damage (diaphragm, quadriceps, and white gastrocnemius). Results Pathway‐specific analyses revealed that Complex I‐supported maximal H 2 O 2 emission was elevated concurrent with a reduced ability of ADP to attenuate emission during respiration in all three muscles (mH 2 O 2 : +17 to +197% in D2. mdx vs. wild type). This was associated with an impaired ability of ADP to stimulate respiration at sub‐maximal and maximal kinetics (−17 to −72% in D2. mdx vs. wild type), as well as a loss of creatine‐dependent mitochondrial phosphate shuttling in diaphragm and quadriceps. These changes largely occurred independent of mitochondrial density or abundance of respiratory chain complexes, except for quadriceps. This muscle was also the only one exhibiting decreased calcium retention capacity, which indicates increased sensitivity to calcium‐induced permeability transition pore opening. Increased H 2 O 2 emission was accompanied by a compensatory increase in total glutathione, while oxidative stress markers were unchanged. Mitochondrial b...

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“…Gaucher's disease Defect BECN1 Impairment of autophagy lysosome pathway 18,19 Pompe disease Defect ATG7 Deficiency of lysosomal enzyme [20][21][22][23] Desminopathies Defect DES Cytoskeletal derangement and accumulation of aggregated proteins 24…”

mentioning

confidence: 99%

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

Sui

Zhang

et al. 2019

Medicinal Research Reviews

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Autophagy is central to the maintenance of intracellular homeostasis across species. Accordingly, autophagy disorders are linked to a variety of diseases from the embryonic stage until death, and the role of autophagy as a therapeutic target has been widely recognized. However, autophagy‐associated therapy for human diseases is still in its infancy and is supported by limited evidence. In this review, we summarize the landscape of autophagy‐associated diseases and current autophagy modulators. Furthermore, we investigate the existing autophagy‐associated clinical trials, analyze the obstacles that limit their progress, offer tactics that may allow barriers to be overcome along the way and then discuss the therapeutic potential of autophagy modulators in clinical applications.

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Combined aerobic exercise and enzyme replacement therapy rejuvenates the mitochondrial–lysosomal axis and alleviates autophagic blockage in Pompe disease

Cited by 28 publications

References 94 publications

Regulation of the autophagy system during chronic contractile activity-induced muscle adaptations

Regulation of the autophagy system during chronic contractile activity-induced muscle adaptations

Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H₂O₂ emission during impaired oxidative phosphorylation

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

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Combined aerobic exercise and enzyme replacement therapy rejuvenates the mitochondrial–lysosomal axis and alleviates autophagic blockage in Pompe disease

Cited by 28 publications

References 94 publications

Regulation of the autophagy system during chronic contractile activity-induced muscle adaptations

Regulation of the autophagy system during chronic contractile activity-induced muscle adaptations

Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H2O2 emission during impaired oxidative phosphorylation

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

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Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H₂O₂ emission during impaired oxidative phosphorylation