Chicco 2013 Abstract MiP2013 Poster

From Bioblast
Chicco AJ, Claiborne MS, Le CH, Mulligan CM (2013) Remodeling of skeletal muscle mitochondria in response to exercise training in taz shRNA mouse model of human Barth Syndrome. Mitochondr Physiol Network 18.08.


Adam Chicco

MiP2013, Book of Abstracts Open Access

Chicco AJ, Claiborne MS, Le CH, Mulligan CM (2013)

Event: MiPNet18.08_MiP2013

Barth Syndrome is a mitochondrial disease associated with exercise intolerance and cardioskeletal myopathy resulting from mutations in the tafazzin (taz) gene. Taz encodes a phospholipid transacylase believed to be important for the remodeling of cardiolipin and maintaining optimal mitochondrial membrane function. The present study characterized skeletal muscle mitochondrial function and exercise capacity of a new taz shRNA mouse model of Barth Syndrome (90% taz-deficient), and examined the effect of exercise training on these parameters.

Mitochondrial respiratory function was assessed in mitochondria freshly isolated from hindlimb muscles using an Oroboros Oxygraph-2k with pyruvate+malate as substrates. A pre-training treadmill graded exercise test (GXT) revealed profound exercise intolerance in taz mice, which corresponded to reduced respiratory capacity, citrate synthase (CS) and ET-pathway Complex I protein content of muscle mitochondria in the taz vs. age-matched wild-type (WT) mice. Based on the pre-training GXT, exercise training was conducted at 12-17 m/min, 0% grade for 60 min/d, 5 d/wk. Exercise training elicited a 99% increase in GXT run time in the taz mice (P<0.01 vs. pre-training), but failed to increase levels to that of sedentary WT mice.

Unexpectedly, training significantly decreased OXPHOS capacity of isolated muscle mitochondria from exercised mice (WTS: 4993 Β± 371, WTX: 3780 Β± 561, TazS: 2979 Β± 384, TazS: 1828 Β± 525 (pmol/(s*mg), P=0.02 Sed. vs. Ex.), and significantly decreased mitochondrial CS activity in taz mice (WTS: 4.48 Β± 0.51, WTX: 3.87 Β± 0.69, TazS: 3.21 Β± 0.54, TazX: 1.63 Β± 0.69 (RU/g), P=0.01). Training tended to reduce mitochondrial lactate dehydrogenase (LDH) and monocarboxylate transporter 1 (MCT1) activities, MnSOD content, and 4-hydroxnonenal-protein adducts (index of oxidative stress), but tended to increase mitochondrial UCP3 in exercised WT and taz mice. Interestingly, training significantly increased CS activity in total muscle homogenates (WTS: 1.491 Β± 0.112, WTX: 1.792 Β± 0.143, TazS: 1.325 Β± 0.108, TazX: 1.550 Β± 0.143 (RU/g), P=0.05 Sed. v. Ex.), suggesting a training-induced increase in whole-muscle oxidative capacity despite a lower OXPHOS capacity per mg protein of isolated mitochondria. This study indicates that exercise training improves functional capacity of taz deficient mice despite persistent mitochondrial respiratory dysfunction, and induces selective remodeling of mitochondria in skeletal muscle perhaps to mitigate oxidant production from a dysfunctional respiratory system while adapting to increased metabolic demand.

β€’ O2k-Network Lab: US CO Fort Collins Chicco AJ

Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Genetic knockout;overexpression, Exercise physiology;nutrition;life style, mt-Medicine  Pathology: Cardiovascular, Myopathy  Stress:Oxidative stress;RONS  Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Isolated mitochondria  Enzyme: Marker enzyme, Uncoupling protein 

Coupling state: OXPHOS  Pathway:HRR: Oxygraph-2k 


Affiliations and author contributions

1 - Mitochondrial Physiology Laboratory, Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, USA;

2 - Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA;

3 - Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.

Email: [email protected]


  1. Soustek MS, Falk DJ, Mah CS, Toth MJ, Schlame M, Lewin AS, Byrne BJ (2011) Characterization of a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency. Hum Gene Ther 22: 865-871.
  2. Spencer CT, Bryant RM, Day J, Gonzalez IL, Colan SD, Thompson WR, Berthy J, Redfearn SP, Byrne BJ (2006) Cardiac and clinical phenotype in Barth syndrome. Pediatrics 118: e337-346.
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