Mitochondrial respiratory capacity and coupling control decline with age in human skeletal muscle

Mitochondrial health is critical to physiological function, particularly in tissues with high ATP turnover, such as striated muscle. It has been postulated that derangements in skeletal muscle mitochondrial function contribute to impaired physical function in older adults. Here, we determined mitochondrial respiratory capacity and coupling control in skeletal muscle biopsies obtained from young and older adults. Twenty-four young (28 ± 7 yr) and thirty-one older (62 ± 8 yr) adults were studied. Mitochondrial respiration was determined in permeabilized myofibers from the vastus lateralis after the addition of substrates oligomycin and CCCP. Thereafter, mitochondrial coupling control was calculated. Maximal coupled respiration (respiration linked to ATP production) was lower in muscle from older vs. young subjects ( P < 0.01), as was maximal uncoupled respiration ( P = 0.06). Coupling control in response to the ATP synthase inhibitor oligomycin was lower in older adults ( P < 0.05), as was the mitochondria flux control ratio, coupled respiration normalized to maximal uncoupled respiration ( P < 0.05). Calculation of respiratory function revealed lower respiration linked to ATP production ( P < 0.001) and greater reserve respiration ( P < 0.01); i.e., respiratory capacity not used for phosphorylation in muscle from older adults. We conclude that skeletal muscle mitochondrial respiratory capacity and coupling control decline with age. Lower respiratory capacity and coupling efficiency result in a reduced capacity for ATP production in skeletal muscle of older adults.

Download Full-text

Leucine augments specific skeletal muscle mitochondrial respiratory pathways during recovery following 7 days of physical inactivity in older adults

Journal of Applied Physiology ◽

10.1152/japplphysiol.00810.2020 ◽

2021 ◽

Author(s):

Emily J. Arentson-Lantz ◽

Jasmine Mikovic ◽

Nisha Bhattarai ◽

Christopher S. Fry ◽

Séverine Lamon ◽

...

Keyword(s):

Older Adults ◽

Skeletal Muscle ◽

Body Weight ◽

Insulin Sensitivity ◽

Bed Rest ◽

Metabolic Clearance ◽

Leucine Supplementation ◽

Respiratory Capacity ◽

Antioxidant Defense Systems ◽

Mitochondrial Respiratory

Leucine supplementation attenuates the loss of skeletal muscle mass and function in older adults during bed rest. We sought to determine if leucine could also preserve and/or restore mitochondrial function and muscle oxidative capacity during periods of disuse and rehabilitation. Healthy older adults (69.1 ± 1.1 years) consumed a structured diet with supplemental leucine (LEU: 0.06 g/ kg body weight/ meal; n=8) or alanine (CON: 0.06 g/ kg body weight/meal; n=8) during 7 days of bed rest and 5 days of inpatient rehabilitation. A 75 g oral glucose tolerance test was performed at baseline (PreBR), after bed rest (PostBR) and rehabilitation (PostRehab) and used to calculate an indicator of insulin sensitivity, metabolic clearance rate. (MCR). Tissue samples from the m. vastus lateralis were collected PreBR, PostBR, and PostRehab to assess mitochondrial respiratory capacity and protein markers of the oxidative phosphorylation and a marker of the antioxidant defense systems. During bed rest, leucine tended to preserve insulin sensitivity (Change in MCR, CON vs. LEU: -3.5 ± 0.82 vs LEU: -0.98 ± 0.88, p=0.054), but had no effect on mitochondrial respiratory capacity (Change in State 3+succinate CON vs. LEU -8.7 ± 6.1 vs. 7.3 ± 4.1 pmol O2/sec/mg tissue, p=0.10) Following rehabilitation, leucine increased ATP-linked respiration (CON vs. LEU: -8.9 ± 6.2 vs. 15.5± 4.4 pmol O2/sec/mg tissue, p=0.0042). While the expression of mitochondrial respiratory and antioxidant proteins was not impacted, leucine supplementation preserved specific pathways of mitochondrial respiration, insulin sensitivity and a marker of oxidative stress during bed rest and rehabilitation.

Download Full-text

Atorvastatin impairs liver mitochondrial function in obese Göttingen Minipigs but heart and skeletal muscle are not affected

Scientific Reports ◽

10.1038/s41598-021-81846-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Liselotte Bruun Christiansen ◽

Tine Lovsø Dohlmann ◽

Trine Pagh Ludvigsen ◽

Ewa Parfieniuk ◽

Michal Ciborowski ◽

...

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Function ◽

Citrate Synthase ◽

Obese Group ◽

Control Group ◽

Dependent Manner ◽

Respiratory Capacity ◽

Protein Carbonyl Content ◽

Functional Changes ◽

Mitochondrial Respiratory

AbstractStatins lower the risk of cardiovascular events but have been associated with mitochondrial functional changes in a tissue-dependent manner. We investigated tissue-specific modifications of mitochondrial function in liver, heart and skeletal muscle mediated by chronic statin therapy in a Göttingen Minipig model. We hypothesized that statins enhance the mitochondrial function in heart but impair skeletal muscle and liver mitochondria. Mitochondrial respiratory capacities, citrate synthase activity, coenzyme Q10 concentrations and protein carbonyl content (PCC) were analyzed in samples of liver, heart and skeletal muscle from three groups of Göttingen Minipigs: a lean control group (CON, n = 6), an obese group (HFD, n = 7) and an obese group treated with atorvastatin for 28 weeks (HFD + ATO, n = 7). Atorvastatin concentrations were analyzed in each of the three tissues and in plasma from the Göttingen Minipigs. In treated minipigs, atorvastatin was detected in the liver and in plasma. A significant reduction in complex I + II-supported mitochondrial respiratory capacity was seen in liver of HFD + ATO compared to HFD (P = 0.022). Opposite directed but insignificant modifications of mitochondrial respiratory capacity were seen in heart versus skeletal muscle in HFD + ATO compared to the HFD group. In heart muscle, the HFD + ATO had significantly higher PCC compared to the HFD group (P = 0.0323). In the HFD group relative to CON, liver mitochondrial respiration decreased whereas in skeletal muscle, respiration increased but these changes were insignificant when normalizing for mitochondrial content. Oral atorvastatin treatment in Göttingen Minipigs is associated with a reduced mitochondrial respiratory capacity in the liver that may be linked to increased content of atorvastatin in this organ.

Download Full-text

Cytochrome c Oxidase Rather than Cytochrome c is a Major Determinant of Mitochondrial Respiratory Capacity in Skeletal Muscle of Aged Rats: Role of Carnitine and Lipoic Acid

Rejuvenation Research ◽

10.1089/rej.2007.0541 ◽

2007 ◽

Vol 10 (3) ◽

pp. 311-326 ◽

Cited By ~ 4

Author(s):

Jayavelu Tamilselvan ◽

Kumarasamy Sivarajan ◽

Muthuswamy Anusuyadevi ◽

Chinnakkannu Panneerselvam

Keyword(s):

Skeletal Muscle ◽

Cytochrome C ◽

Cytochrome C Oxidase ◽

Lipoic Acid ◽

Major Determinant ◽

Aged Rats ◽

Respiratory Capacity ◽

Mitochondrial Respiratory

Download Full-text

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00159.2011 ◽

2012 ◽

Vol 302 (6) ◽

pp. E731-E739 ◽

Cited By ~ 81

Author(s):

Maria H. Holmström ◽

Eduardo Iglesias-Gutierrez ◽

Juleen R. Zierath ◽

Pablo M. Garcia-Roves

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Mitochondrial Respiration ◽

Mitochondrial Dynamics ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Respiratory Capacity ◽

Tissue Specific ◽

Mitochondrial Respiratory

The tissue-specific role of mitochondrial respiratory capacity in the development of insulin resistance and type 2 diabetes is unclear. We determined mitochondrial function in glycolytic and oxidative skeletal muscle and liver from lean (+/ ?) and obese diabetic ( db/db) mice. In lean mice, the mitochondrial respiration pattern differed between tissues. Tissue-specific mitochondrial profiles were then compared between lean and db/db mice. In liver, mitochondrial respiratory capacity and protein expression, including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), was decreased in db/db mice, consistent with increased mitochondrial fission. In glycolytic muscle, mitochondrial respiration, as well as protein and mRNA expression of mitochondrial markers, was increased in db/db mice, suggesting increased mitochondrial content and fatty acid oxidation capacity. In oxidative muscle, mitochondrial complex I function and PGC-1α and mitochondrial transcription factor A (TFAM) protein levels were decreased in db/db mice, along with increased level of proteins related to mitochondrial dynamics. In conclusion, mitochondrial respiratory performance is under the control of tissue-specific mechanisms and is not uniformly altered in response to obesity. Furthermore, insulin resistance in glycolytic skeletal muscle can be maintained by a mechanism independent of mitochondrial dysfunction. Conversely, insulin resistance in liver and oxidative skeletal muscle from db/db mice is coincident with mitochondrial dysfunction.

Download Full-text

CHRONIC PRESSURE OVERLOAD IN RATS REDUCES MITOCHONDRIAL RESPIRATORY CAPACITY BUT NOT COUPLING TO ATP-PRODUCTION

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(11)60292-1 ◽

2011 ◽

Vol 57 (14) ◽

pp. E292

Author(s):

Andrea Schrepper ◽

Michael Schwarzer ◽

Paulo A. Amorim ◽

Gloria Faerber ◽

Torsten Doenst

Keyword(s):

Pressure Overload ◽

Respiratory Capacity ◽

Atp Production ◽

Mitochondrial Respiratory

Download Full-text

Mitochondrial Respiratory Capacity and Coupling Control of Skeletal Muscle in Colon-26 Tumor-Induced Cachexia

Medicine & Science in Sports & Exercise ◽

10.1249/01.mss.0000535732.23084.f4 ◽

2018 ◽

Vol 50 (5S) ◽

pp. 197

Author(s):

Jessica L. Halle ◽

Gabriel S. Pena ◽

Hector G. Paez ◽

Joseph P. Carzoli ◽

Michael C. Zourdos ◽

...

Keyword(s):

Skeletal Muscle ◽

Respiratory Capacity ◽

Colon 26 ◽

Mitochondrial Respiratory

Download Full-text

Exercise Is Required to Improve Mitochondrial Respiratory Capacity in Skeletal Muscle of Older Obese Subjects during Calorie Restriction–Induced Weight Loss to Improve Insulin Sensitivity

Diabetes ◽

10.2337/db18-1907-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1907-P

Author(s):

GIOVANNA DISTEFANO ◽

ROBERT STANDLEY ◽

ELVIS A. CARNERO ◽

PAUL M. COEN ◽

RICK B. VEGA ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Insulin Sensitivity ◽

Calorie Restriction ◽

Improve Insulin Sensitivity ◽

Respiratory Capacity ◽

Obese Subjects ◽

Mitochondrial Respiratory

Download Full-text

Constitutively active calcineurin in skeletal muscle increases endurance performance and mitochondrial respiratory capacity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00403.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. E8-E16 ◽

Cited By ~ 36

Author(s):

Lake Q. Jiang ◽

Pablo M. Garcia-Roves ◽

Thais de Castro Barbosa ◽

Juleen R. Zierath

Keyword(s):

Skeletal Muscle ◽

Energy Expenditure ◽

Transgenic Mice ◽

Exercise Performance ◽

Endurance Performance ◽

Wild Type ◽

Respiratory Capacity ◽

Edl Muscle ◽

Mitochondrial Respiratory ◽

Constitutively Active

Expression of an activated form of calcineurin in skeletal muscle selectively up-regulates slow-fiber-specific gene expression. Here, we tested the hypothesis that expression of activated calcineurin in skeletal muscle influences body composition, energy homeostasis, and exercise performance. Using transgenic mice expressing activated calcineurin (CnA*) in skeletal muscle (MCK-CnA* transgenic mice), we determined whether skeletal muscle reprogramming by calcineurin activation affects exercise performance and skeletal muscle mitochondrial function. Body weight and extensor digitorum longus (EDL) skeletal muscle weight were reduced 10% in MCK-CnA* mice compared with wild-type littermates. Basal oxygen consumption, food intake, and voluntary exercise behavior were unchanged between MCK-CnA* and wild-type mice. However, when total energy expenditure was normalized by fat-free mass, energy expenditure was increased in MCK-CnA* mice. An endurance performance treadmill running test revealed MCK-CnA* mice are fatigue resistant and run 50% farther before exhaustion. After a standardized exercise bout, glycogen and triglyceride content in EDL muscle was higher in MCK-CnA* vs. wild-type mice. Mitochondrial respiratory capacity was increased 35% in EDL muscle from resting MCK-CnA* mice. In conclusion, our results provide evidence to support the hypothesis that calcineurin activation in skeletal muscle increases mitochondrial oxidative function and energy substrate storage, which contributes to enhanced endurance exercise performance. These adaptive changes occur as a consequence of a lifelong expression of a constitutively active calcineurin and mimic the response to chronic endurance training.

Download Full-text