Effects of OXPHOS complex deficiencies and ESA dysfunction in working intact skeletal muscle: implications for mitochondrial myopathies

Primary mitochondrial myopathies (PMM) are a group of mitochondrial disorders characterized by a predominant skeletal muscle involvement. The aim of this study was to evaluate whether the biochemical profile determined by Fourier-transform infrared (FTIR) spectroscopic technique would allow to distinguish among patients affected by progressive external ophthalmoplegia (PEO), the most common PMM presentation, oculopharyngeal muscular dystrophy (OPMD), and healthy controls. Thirty-four participants were enrolled in the study. FTIR spectroscopy was found to be a sensitive and specific diagnostic marker for PEO. In particular, FTIR spectroscopy was able to distinguish PEO patients from those affected by OPMD, even in the presence of histological findings similar to mitochondrial myopathy. At the same time, FTIR spectroscopy differentiated single mtDNA deletion and mutations in POLG, the most common nuclear gene associated with mitochondrial diseases, with high sensitivity and specificity. In conclusion, our data suggest that FTIR spectroscopy is a valuable biodiagnostic tool for the differential diagnosis of PEO with a high ability to also distinguish between single mtDNA deletion and mutations in POLG gene based on specific metabolic transitions.

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Mechanisms of the effect of oxidative phosphorylation deficiencies on the skeletal muscle bioenergetic system in patients with mitochondrial myopathies

Journal of Applied Physiology ◽

10.1152/japplphysiol.00196.2021 ◽

2021 ◽

Author(s):

Bernard Korzeniewski

Keyword(s):

Skeletal Muscle ◽

Oxidative Phosphorylation ◽

Muscle Fatigue ◽

Exercise Intolerance ◽

Kinetic Properties ◽

Work Intensity ◽

Mitochondrial Myopathies ◽

Threshold Mechanism ◽

Kinetic Effects ◽

Double Threshold

Simulations carried out using a previously-developed model of the skeletal muscle bioenergetic system, involving the "Pi double-threshold" mechanism of muscle fatigue, lead to the conclusion that a decrease in the oxidative phosphorylation (OXPHOS) activity, caused by mutations in mitochondrial or nuclear DNA, is the main mechanism underlying the changes in the kinetic properties of the system in mitochondrial myopathies (MM). These changes generally involve the very-heavy-exercise-like behavior and exercise termination because of fatigue at low work intensities. In particular, a sufficiently large (at a given work intensity) decrease in OXPHOS activity leads to slowing of the primary phase II of the V̇O2 on-kinetics, decrease in V̇O2max, appearance of the slow component of the V̇O2 on-kinetics, exercise intolerance and lactic acidosis at relatively low power outputs encountered in experimental studies in MM patients. Thus, the "Pi double-threshold" mechanism of muscle fatigue is able to account, at least semi-quantitatively, for various kinetic effects of inborn OXPHOS deficiencies of the skeletal muscle bioenergetic system. Exercise can be potentially lengthened and V̇O2max elevated in MM patients through an increase in peak Pi (Pipeak), at which exercise is terminated because of fatigue. Generally, a mechanism underlying the kinetic effects of OXPHOS deficiencies on the skeletal muscle bioenergetic system in MM is proposed that was absent in the literature.

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Mice lacking COX10 in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency

Human Molecular Genetics ◽

10.1093/hmg/ddi307 ◽

2005 ◽

Vol 14 (18) ◽

pp. 2737-2748 ◽

Cited By ~ 98

Author(s):

Francisca Diaz ◽

Christine K. Thomas ◽

Sofia Garcia ◽

Dayami Hernandez ◽

Carlos T. Moraes

Keyword(s):

Skeletal Muscle ◽

Cytochrome C ◽

Cytochrome C Oxidase ◽

Mitochondrial Myopathies ◽

Oxidase Deficiency ◽

Cytochrome C Oxidase Deficiency

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Exogenous coenzyme Q (CoQ) fails to increase CoQ in skeletal muscle of two patients with mitochondrial myopathies

Journal of the Neurological Sciences ◽

10.1016/0022-510x(90)90075-x ◽

1990 ◽

Vol 95 (3) ◽

pp. 283-290 ◽

Cited By ~ 24

Author(s):

Stephan Zierz ◽

Ortgies von Wersebe ◽

Johannes Bleistein ◽

Felix Jerusalem

Keyword(s):

Skeletal Muscle ◽

Coenzyme Q ◽

Mitochondrial Myopathies

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Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies

BMC Genomics ◽

10.1186/1471-2164-15-91 ◽

2014 ◽

Vol 15 (1) ◽

pp. 91 ◽

Cited By ~ 55

Author(s):

Susana Kalko ◽

Sonia Paco ◽

Cristina Jou ◽

Maria Rodríguez ◽

Marija Meznaric ◽

...

Keyword(s):

Skeletal Muscle ◽

Human Skeletal Muscle ◽

Signalling Pathway ◽

Mitochondrial Myopathies ◽

Transcriptomic Profiling ◽

Differentiation Factor

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Effects of β-hydroxy-β-methylbutyrate on skeletal muscle mitochondrial content and dynamics, and lipids after 10 days of bed rest in older adults

Journal of Applied Physiology ◽

10.1152/japplphysiol.00192.2017 ◽

2017 ◽

Vol 123 (5) ◽

pp. 1092-1100 ◽

Cited By ~ 20

Author(s):

Robert A. Standley ◽

Giovanna Distefano ◽

Suzette L. Pereira ◽

Min Tian ◽

Owen J. Kelly ◽

...

Keyword(s):

Older Adults ◽

Skeletal Muscle ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Vastus Lateralis ◽

Bed Rest ◽

Disuse Atrophy ◽

Mitochondrial Content ◽

Cross Sectional ◽

Oxphos Complex

Loss of muscle mass during periods of disuse likely has negative health consequences for older adults. We have previously shown that β-hydroxy-β-methylbutyrate (HMB) supplementation during 10 days of strict bed rest (BR) attenuates the loss of lean mass in older adults. To elucidate potential molecular mechanisms of HMB effects on muscle during BR and resistance training rehabilitation (RT), we examined mediators of skeletal muscle mitochondrial dynamics, autophagy and atrophy, and intramyocellular lipids. Nineteen older adults (60–76 yr) completed 10 days BR followed by 8-wk RT rehabilitation. Subjects were randomized to either HMB (3 g/day HMB; n = 11) or control (CON; n = 8) groups. Skeletal muscle cross-sectional area (CSA) was determined by histology from percutaneous vastus lateralis biopsies. We measured protein markers of mitochondrial content [oxidative phosphorylation (OXPHOS)], fusion and fission (MFN2, OPA1, FIS1, and DRP1), autophagy (Beclin1, LC3B, and BNIP3), and atrophy [poly-ubiquinated proteins (poly-ub)] by Western blot. Fatty acid composition of several lipid classes in skeletal muscle was measured by infusion-MS analysis. Poly-ub proteins and OXPHOS complex I increased in both groups following BR ( P < 0.05, main effect for time), and muscle triglyceride content tended to increase following BR in the HMB group ( P = 0.055). RT rehabilitation increased OXPHOS complex II protein ( P < 0.05), and total OXPHOS content tended ( P = 0.0504) to be higher in HMB group. In addition, higher levels of DRP1 and MFN2 were maintained in the HMB group after RT ( P < 0.05). BNIP3 and poly-ub proteins were significantly reduced following rehabilitation in both groups ( P < 0.05). Collectively, these data suggest that HMB influences mitochondrial dynamics and lipid metabolism during disuse atrophy and rehabilitation. NEW & NOTEWORTHY Mitochondrial content and dynamics remained unchanged over 10 days of BR in older adults. HMB stimulated intramuscular lipid storage as triacylglycerol following 10 days of bed rest (BR) and maintained higher mitochondrial OXPHOS content and dynamics during the 8-wk resistance exercise rehabilitation program.

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Application of nile blue and nile red, two fluorescent probes, for detection of lipid droplets in human skeletal muscle.

Journal of Histochemistry & Cytochemistry ◽

10.1177/35.5.3559182 ◽

1987 ◽

Vol 35 (5) ◽

pp. 619-621 ◽

Cited By ~ 39

Author(s):

E Bonilla ◽

A Prelle

Keyword(s):

Skeletal Muscle ◽

Fluorescent Probes ◽

Lipid Droplets ◽

Nile Blue ◽

Muscle Fibers ◽

Nile Red ◽

Normal Muscle ◽

Mitochondrial Myopathies ◽

Muscle Lipid ◽

Muscle Biopsies

Using frozen sections from human muscle biopsies, we assessed the value of Nile blue and Nile red, two fluorescent probes, as stains for lipid droplets in normal and pathological skeletal muscle fibers. In normal muscle, lipid storage disorders, and mitochondrial myopathies, Nile blue stained the lipid droplets as yellow-gold fluorescent structures. The lipid droplets were also seen as yellow-gold fluorescent structures in Nile red-stained sections, but the outstanding feature in these preparations was the staining of the membrane network of the muscle fibers and membrane proliferations in pathological muscle as red-orange fluorescent structures. These results suggest that both Nile blue and Nile red stains are useful for visualization of lipid droplets and membrane proliferations in pathological muscle biopsies.

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