Mitochondrial Succinate Dehydrogenase in Chronic Obstructive Pulmonary Disease: Is Complex II Too Complex?

Chronic obstructive pulmonary disease (COPD) is best known for its limiting effects on expiratory airflow in the lung. However, COPD affects more than just the lung, as patients with this disease also develop systemic disorders that contribute significantly to morbidity and mortality. One of these comorbidities involves skeletal muscle weakness, which can impair ambulation and affect the respiratory muscles, including the diaphragm. Skeletal muscle dysfunction significantly degrades quality of life and worsens clinical outcomes by increasing the frequency of exacerbations and associated hospitalizations, which, in turn, accelerate disease progression (1).

Muscle function is characterized by muscle fiber strength, the ability to generate contractile force, and muscle endurance, the ability to sustain a degree of continuous activity without developing fatigue. Healthy muscles are often made up of a range of fiber types that differ with respect to their speed of contraction, ability to develop force, and endurance capacity. Differences in fiber phenotype arise from cell-specific differences in expression of contractile fiber genes, mitochondrial content, oxidative and glycolytic capacity, calcium sensitivity, and other characteristics. Importantly, the fiber phenotype can change in response to exercise training or disuse and can also change in response to diseases, including COPD. Loss of muscle function can occur through atrophy (muscle wasting from disuse), cachexia (wasting often associated with cancer), and sarcopenia (wasting associated with aging). Understanding of the mechanisms that contribute to muscle dysfunction in COPD is complicated by the fact that disuse, aging, and other diseases such as cancer, malnutrition, heart failure, or diabetes can contribute to the composite muscle dysfunction in COPD. For unknown reasons, the severity of muscle wasting in emphysema is frequently more severe than with chronic bronchitis (2). Moreover, changes in chest wall geometry in advanced emphysema can lessen ventilatory muscle efficiency in the diaphragm and the chest wall, thereby worsening the functional consequences of muscle fiber weakness (3). Other factors remaining the same, a shift in the fiber type composition of a muscle can also induce dysfunction. For example, a shift toward a fast glycolytic phenotype can lessen endurance capacity and increase likelihood of fatigue in a muscle that normally contracts repeatedly. Pulmonary rehabilitation, which includes exercise training of muscles involved in ventilation as well as ambulation, is currently the most effective treatment for muscle dysfunction in patients with COPD.

At present, the molecular mechanisms responsible for muscle dysfunction in COPD are not well understood. Analysis of muscle fibers from patients with COPD is complicated by limited access to live muscle specimens and is compounded by the fact that the metabolic demands of resting muscle cells in culture are significantly less than those of working fibers. Progress will likely arise from animal models that recapitulate the patterns of muscle dysfunction associated with COPD and that develop muscle dysfunction after the onset of airflow limitation. In this issue of the Journal, Balnis and colleagues (pp. 259–271) describe their approach to this challenge using a transgenic mouse model with inducible lung IL-13 expression that results in the development of lung emphysema (4).

Extensor digitorum longus (EDL) muscles from these mice had previously been shown to undergo decreases in fiber cross-sectional area, force generation capacity, and resistance to fatigue (5). As endurance capacity is linked to mitochondrial oxidative phosphorylation, they measured the oxygen consumption rate (OCR) and found that it was decreased compared with wild-type control animals, even though mitochondrial ultrastructure, fiber type composition, and mitochondrial mass were not different. Previous proteomic studies of EDL muscles from patients with COPD had identified decreases in bioenergetic-related proteins, which led these investigators to identify mitochondrial SDHC (succinate dehydrogenase subunit C) as being downregulated in the IL-13 mouse muscles (5). This was associated with decreased SDH (complex II) enzymatic capacity despite the presence of ample succinate. Importantly, respiratory capacity at complex IV—downstream from complex II—was not diminished. These findings suggested that the reduced oxidative function in the COPD EDL muscles was due to a functional deficit in complex II.

Balnis and colleagues identified an ∼25% reduction in maximal SDH function. Curiously, type II fibers are typically capable of increasing OCR more than 10-fold at maximal exercise compared with resting rates. Could this modest decrease in SDHC capacity explain the measured decrease in resting OCR? To test this, they suppressed SDHC expression in C2C12 mouse myoblasts to mimic the decrease seen in EDL muscle and found that this decreased resting OCR was consistent with the conclusion that the decrease in SDHC could explain the low resting OCR and, potentially, a decline of in vivo muscle function.

Next, in a well-designed experiment, they sought to rescue SDHC expression in vivo, using electroporation of tibialis anterior muscle with an SDHC expression plasmid on one side of the animal and a control plasmid on the contralateral side. This rescued the ex vivo OCR in the SDHC muscle compared with the control side. The endurance capacity of EDL muscle from IL-13 mice was also improved by SDHC transfection. These experiments identify a loss of SDHC as an important contributor to the impaired OCR and fatigue resistance that were observed in the emphysematous mice. Finally, they found that SDHC-expressing fibers from IL-13 mice exhibited an increase in type 2A and 2X fiber types and a decrease in type 2B, indicating that mitochondrial SDH function can regulate muscle fiber phenotype in vivo, thus demonstrating that mitochondrial function controls fiber gene transcription related to its phenotype.

These remarkable findings further underscore the importance of mitochondria in cellular functions that go beyond ATP production (5, 6). However, several key questions remain. First, how does emphysema produce a selective decrease in SDHC expression in muscle? The expression of mitochondrial complex subunits is an elegantly orchestrated symphony involving coordinated translation of nuclear- and mitochondria-encoded genes at times and levels that permit mitochondrial biogenesis while avoiding the mitochondrial stress that can arise from an imbalance in the abundance of one subunit relative to other components of the same complex. The mechanism by which COPD disrupts a single instrument in that symphony is unknown.

Another challenge is to identify how altered SDH function—caused by deficiency in SDHC—affects muscle cell performance and phenotype. As the authors point out, several candidate mechanisms include 1) reactive oxygen species (ROS) generation, 2) protein posttranslational modifications, and 3) epigenetic regulation. Regarding the first, loss of SDH subunits B, C, or D leads to an increase in ROS generation from the SDH A subunit (7). If mitochondrial ROS signals disrupt muscle function and phenotype, then mitochondria-targeted ROS scavengers might prove effective in preventing the muscle cell dysfunction. Regarding the second mechanism, the authors detected an increase in cellular succinate levels, which was consistent with the observed decrease in SDH function. This intermediate of the tricarboxylic acid cycle can act as a substrate for protein succinylation, which can alter protein structure and function. Finally, succinate can affect epigenetic regulation by acting as an inhibitor of protein and DNA demethylases by competing with the normal substrate, 2-oxoglutarate (8). This can have significant consequences in terms of chromatin structure and gene expression. In a similar manner, succinate can inhibit prolyl hydroxylases by competing with 2-oxoglutarate, resulting in aberrant regulation of hypoxia-inducible factor transcriptional activity. Each of these mechanisms will need to be explored in future studies.

Although therapeutic rescue of SDHC expression in patients with COPD is an exciting possibility, in vivo gene transfer of SDHC as a therapeutic modality faces many challenges. An understanding of how and which signals—presumably originating in the emphysematous lung—disrupt SDHC expression in muscle might open the door to novel therapies. It might be more feasible to intercept those signals and thereby prevent the SDHC dysregulation as opposed to correcting the defect after it has developed.