Author(s): GUTIERREZ, S., CAMPOS, C., CABELLO-VERRUGIO, C., PARADA, P., MEYER, T., JALÓN, M., VALLADARES-IDE, D., PEÑAILILLO, P., Institution: UNIVERSITY ANDRÉS BELLO, Country: CHILE, Abstract-ID: 2461

INTRODUCTION:
Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, and lower-limb muscle dysfunction represents a major extrapulmonary manifestation (1). Systemic inflammation induces skeletal muscle dysfunction in COPD, which is characterized by mitochondrial dysfunction and reduced muscle mass, strength, and aerobic capacity (2). Circulating inflammatory molecules can activate the GADD45A/MEKK4 protein complex in skeletal muscle, which has been associated with muscle atrophy and mitochondrial dysfunction (3), suggesting a potential role in COPD-related muscle impairment. This study aimed to compare the total protein content of GADD45A/MEKK4 protein, synthesis/degradation pathways, and mitochondrial proteins, and their association with muscle function in patients with severe COPD and healthy participants.
METHODS:
Six severe COPD (64.9±5.6 y; Forced expiratory volume in 1 second; FEV1 =37.5±13.6% of predicted) and six healthy participants (61.7±5.3 y; FEV1=110.58±13.6% of predicted) underwent knee extensor maximal isometric voluntary contraction (MVC) and maximal aerobic capacity (VO2peak) testing. Blood samples were collected to determine ultrasensitive C-reactive protein (CRP) levels. A muscle biopsy from the vastus lateralis was collected to determine GADD45A, MEKK4, NF-kB, total ubiquitination, mTOR, p70s6K, PGC-1α, OXPHOS, COX-IV, mitofusin2, and DRP1 total protein content from whole-muscle homogenates.
RESULTS:
COPD showed 23.8% (p<0.01) and 34.7% (p<0.01) lesser MVC and VO2peak, respectively. CRP levels in blood samples were 15-fold higher in COPD patients compared with healthy participants. GADD45A/total protein was similar in both groups (p=0.84), but MEKK4/total protein was 34.9% greater (p=0.02), and the ratio p-NF-kB/NF-kB was 5-fold greater in COPD patients compared with healthy participants. COPD showed a 35.7% lower level of p70S6k/total protein (p=0.02) than healthy individuals, with no differences in mTOR (p=0.56) and total protein ubiquitination (p=0.63). COPD showed 13-130% lesser levels of all OXPHOS subunits (p<0.01). DRP1/total protein levels were 195.8% greater (p<0.01) in COPD compared to healthy individuals, with no difference found in mitofusin2/total protein. Interestingly, COPD patients showed 82.1% greater levels of PGC-1α/total protein (p=0.03). GADD45A was positively associated with CRP (r = 0.58, p=0.01) and leg fat mass (r = 0.65, p=), whereas MEKK4 was positively associated with muscle strength (r = 0.68, p=0.01), mitochondrial complex II (r = 0.71, p=0.01), complex III (r = 0.56, p=0.01), and PGC-1α (r = 0.67, p=0.01).
CONCLUSION:
These results confirm systemic inflammation and muscle dysfunction in patients with COPD. GADD45A shows a tendency to be elevated in COPD, while MEKK4 appears to be higher in healthy controls. GADD45A content is associated with increased CRP and fat mass in the legs in patients with COPD, while decreased MEKK4 levels may be related to lower levels of mitochondrial complex proteins.