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ABSTRACT: While it is well established that the lack of myostatin (Mstn) promotes skeletal muscle hypertrophy, the corresponding changes regarding force generation have been mainly studied in vitro and remain conflicting. Furthermore, the metabolic underpinnings of these changes are very poorly documented. To clarify this issue, we have investigated strictly noninvasively in vivo the impact of the lack of Mstn on gastrocnemius muscle function and energetics in Mstn-targeted knockout (Mstn(-/-)) mice using 1H-magnetic resonance (MR) imaging and 31P-MR spectroscopy during maximal repeated isometric contractions induced by transcutaneous electrostimulation. In Mstn(-/-) animals, although body weight, gastrocnemius muscle volume and absolute force were larger (+ 38 %, + 118 % and + 34 %, respectively) compared to wild-type (Mstn(+/+)) mice, specific force (calculated from MR imaging measurements) was significantly lower (- 36 %) and resistance to fatigue was decreased. Besides, Mstn deficiency did not affect phosphorylated compound concentrations and intracellular pH at rest, but caused a large increase in ATP cost of contraction (up to + 206 % compared to Mstn(+/+)) throughout the stimulation period. Further, Mstn deficiency limits the shift toward oxidative metabolism during muscle activity despite oxidative ATP synthesis capacity was not altered. Our data demonstrate in vivo that the absence of Mstn impairs both mechanical performance and energy cost of contraction in hypertrophic muscle. These findings must be kept in mind when considering Mstn as a potential therapeutic target for increasing muscle mass in patients suffering from muscle-wasting disorders.
AJP Endocrinology and Metabolism 04/2013; · 4.75 Impact Factor
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Sarah Oddoux,
Julie Brocard,
Annie Schweitzer,
Peter Szentesi, Benoit Giannesini,
Jacques Brocard,
Julien Fauré,
Karine Pernet-Gallay,
David Bendahan,
Joël Lunardi,
Laszlo Csernoch,
Isabelle Marty
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ABSTRACT: Triadin is a multiple proteins family, some isoforms being involved in muscle excitation-contraction coupling, and some having still unknown functions. To obtain clues on triadin functions, we engineered a triadin knock-out mouse line and characterized the physiological effect of triadin ablation on skeletal muscle function. These mice presented a reduced muscle strength, which seemed not to alter their survival and has been characterized in the present work. We first checked in these mice the expression level of the different proteins involved in calcium homeostasis and observed in fast muscles an increase in expression of dihydropyridine receptor, with a large reduction in calsequestrin expression. Electron microscopy analysis of KO muscles morphology demonstrated the presence of triads in abnormal orientation and a reduction in the sarcoplasmic reticulum terminal cisternae volume. Using calcium imaging on cultured myotubes, we observed a reduction in the total amount of calcium stored in the sarcoplasmic reticulum. Physiological studies have been performed to evaluate the influence of triadin deletion on skeletal muscle function. Muscle strength has been measured both on the whole animal model, using hang test or electrical stimulation combined with NMR analysis and strength measurement, or on isolated muscle using electrical stimulation. All the results obtained demonstrate an important reduction in muscle strength, indicating that triadin plays an essential role in skeletal muscle function and in skeletal muscle structure. These results indicate that triadin alteration leads to the development of a myopathy, which could be studied using this new animal model.
Journal of Biological Chemistry 10/2009; 284(50):34918-29. · 4.77 Impact Factor
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ABSTRACT: Although the exact mechanisms are still unclear, it is commonly acknowledged that acute eccentric exercise alters muscle performance, whereas the repetition of successive bouts leads to the disappearance of the deleterious signs. To clarify this issue, we measured blood creatine kinase and lactate dehydrogenase activities and proton transverse relaxation time (T2) in various leg muscles 72 h after single and repeated bouts of exhausting downhill running sessions (-15 degrees , 1.5 km/h) with either 4 or 7 days elapsed between bouts. After a single exercise bout, T2 and enzyme activities initially increased and recovered rapidly. When exercise bouts were repeated over a short time period (4 days), initial changes did not recover and endurance time throughout additional exercise sessions was significantly reduced. On the contrary, with a longer resting time between exercises (7 days), the endurance time of additional running sessions was significantly longer and muscle changes (T2 increase, muscle edema, and enzyme activity changes) slowly and completely reversed. Significant correlations were found between T2 changes and enzyme activities. T2 changes in the soleus and gastrocnemius muscle heads were differently affected by lengthening contractions, suggesting a muscle specificity and indicating that muscle alterations might be linked to different anatomical properties, such as fiber pennation angles, typology, and/or the exhausting nature of the downhill running sessions. We documented a "less muscle injury" effect due to the repetition of exercise bouts at a low frequency (i.e., 1 session per week) in accordance with the delayed muscle inflammation. This effect was not observed when the between-exercise resting time was shorter.
Journal of Applied Physiology 08/2008; 105(1):299-307. · 3.75 Impact Factor
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ABSTRACT: Although depletion in high-energy phosphorylated compounds and mitochondrial impairment have been reported in septic skeletal muscle at rest, their impact on energy metabolism has not been documented during exercise. In this study we aimed to investigate strictly gastrocnemius muscle function non-invasively, using magnetic resonance techniques in endotoxemic rats. Endotoxemia was induced by injecting animals intraperitoneally at t(0) and t(0) + 24 h with Klebsiella pneumoniae lipopolysaccharides (at 3 mg kg(-1)). Investigations were performed at t(0) + 48 h during a transcutaneous electrical stimulation protocol consisting of 5.7 min of repeated isometric contractions at a frequency of 3.3 HZ. Endotoxin treatment produced a depletion in basal phosphocreatine content and a pronounced reduction in oxidative adenosine triphosphate (ATP) synthesis capacity, whereas the resting ATP concentration remained unchanged. During the stimulation period, endotoxemia caused a decrease in force-generating capacity that was fully accounted for by the loss of muscle mass. It further induced an acceleration of glycolytic ATP production and an increased accumulation of adenosine diphosphate (ADP, an important mitochondrial regulator) that allowed a near-normal rate of oxidative ATP synthesis. Finally, endotoxemia did not affect the total rate of ATP production or the ATP cost of contraction throughout the whole stimulation period. These data demonstrate that, in an acute septic phase, metabolic alterations in resting muscle do not impact energy supply in exercising muscle, likely as a result of adaptive mechanisms.
Muscle & Nerve 05/2008; 37(4):496-504. · 2.37 Impact Factor
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ABSTRACT: Traditional setups for in situ MR investigation of skeletal muscle function in animals use invasive systems for muscle stimulation and force measurement. These systems require surgical preparation and therefore exclude repetitive investigations on the same animal. This article describes a new experimental setup allowing strictly noninvasive MR investigations of muscle function in contracting rat gastrocnemius muscle using 1H-MR imaging and 31P-MR spectroscopy. The novelty of this setup is the integration of two noninvasive systems allowing muscle contraction by transcutaneous stimulation and force measurement with a dedicated ergometer. Muscle function was investigated in 20 rats (275-300 g) through a fatiguing stimulation protocol, either with this noninvasive setup (n = 10) or with a traditional MR setup (n = 10). T2-weighted images demonstrated that transcutaneous stimulation activated mainly the gastrocnemius muscle. Moreover, the changes in force development and in energy metabolism obtained with the noninvasive setup were qualitatively and quantitatively similar to those obtained with the traditional setup. This noninvasive setup is thus suitable for investigating skeletal muscle function in situ. It offers the possibility to repeat investigations in the same animal, avoiding individual variability and enabling longitudinal follow-up studies. This opens up new perspectives in various research areas including pharmaceutical research.
Magnetic Resonance in Medicine 12/2005; 54(5):1058-64. · 2.96 Impact Factor
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ABSTRACT: Net phosphocreatine (PCr) resynthesis during muscle contraction is a paradoxical phenomenon because it occurs under conditions of high energy demand. The metabolic underpinnings of this phenomenon were analyzed non-invasively using 31P-magnetic resonance spectroscopy in rat gastrocnemius muscle (n=11) electrically stimulated (7.6 Hz, 6 min duration) in situ under ischemic and normoxic conditions. During ischemic stimulation, [PCr] initially fell to a steady state (9+/-5% of resting concentration) which was maintained for the last 5 min of stimulation, whereas isometric force production decreased to a non-measurable level beyond 3 min. Throughout normoxic stimulation, [PCr] and force production declined to a steady state after respectively 1 min (5+/-3% of resting concentration) and 3.25 min (21+/-8% of initial value) of stimulation. Contrary to the observations under ischemia, a paradoxical net PCr resynthesis was recorded during the last 2 min of normoxic stimulation and was not accompanied by any improvement in force production. These results demonstrate that the paradoxical net PCr resynthesis recorded in contracting muscle relies exclusively on oxidative energy production and could occur in inactivated fibers, similarly to PCr resynthesis during post-exercise recovery.
Biochimica et Biophysica Acta 03/2002; 1553(3):223-31. · 4.66 Impact Factor
