Dataset Information

Diminished muscle oxygen uptake and fatigue in spinal muscular atrophy.

ABSTRACT:

Objective

To estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory individuals with spinal muscular atrophy (SMA) and healthy controls.

Methods

Peak aerobic capacity (VO_2peak ) and workload (W_peak ) were measured by cardiopulmonary exercise test (CPET) in 19 ambulatory SMA patients and 16 healthy controls. Submaximal exercise (SME) at 40% W_peak was performed for 10 minutes. Change in vastus lateralis deoxygenated hemoglobin, measured by near-infrared spectroscopy, determined muscle oxygen uptake (ΔHHb) at rest and during CPET and SME. Dual energy X-ray absorptiometry assessed fat-free mass (FFM%). Fatigue was determined by percent change in workload or distance in the first compared to the last minute of SME (Fatigue_SME ) and six-minute walk test (Fatigue_6MWT ), respectively.

Results

ΔHHb-PEAK, ΔHHb-SME, VO_2peak , W_peak , FFM%, and 6MWT distance were lower (P < 0.001), and Fatigue_6MWT and Fatigue_SME were higher (P < 0.001) in SMA compared to controls. ΔHHb-PEAK correlated with FFM% (r = 0.50) and VO_2peak (r = 0.41) only in controls. Only in SMA, Fatigue_6MWT was inversely correlated with W_peak (r = -0.69), and Fatigue_SME was inversely correlated with FFM% (r = -0.55) and VO_2peak (r = -0.69).

Interpretation

This study provides further support for muscle mitochondrial dysfunction in SMA patients. During exercise, we observed diminished muscle oxygen uptake but no correlation with aerobic capacity or body composition. We also observed increased fatigue which correlated with decreased aerobic capacity, workload, and body composition. Understanding the mechanisms underlying diminished muscle oxygen uptake and increased fatigue during exercise in SMA may identify additional therapeutic targets that rescue symptomatic patients and mitigate their residual disease burden.

SUBMITTER: Montes J

PROVIDER: S-EPMC8108417 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:IMPORTANCE:The important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively). OBJECTIVE:To investigate mitochondrial dysfunction in a large series of muscle biopsy samples from patients with SMA. DESIGN, SETTING, AND PARTICIPANTS:We studied quadriceps muscle samples from 24 patients with genetically documented SMA and paraspinal muscle samples from 3 patients with SMA-II undergoing surgery for scoliosis correction. Postmortem muscle samples were obtained from 1 additional patient. Age-matched controls consisted of muscle biopsy specimens from healthy children aged 1 to 3 years who had undergone analysis for suspected myopathy. Analyses were performed at the Neuromuscular Unit, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico-Milano, from April 2011 through January 2015. EXPOSURES:We used histochemical, biochemical, and molecular techniques to examine the muscle samples. MAIN OUTCOMES AND MEASURES:Respiratory chain activity and mitochondrial content. RESULTS:Results of histochemical analysis revealed that cytochrome-c oxidase (COX) deficiency was more evident in muscle samples from patients with SMA-I and SMA-II. Residual activities for complexes I, II, and IV in muscles from patients with SMA-I were 41%, 27%, and 30%, respectively, compared with control samples (P <?.005). Muscle mtDNA content and cytrate synthase activity were also reduced in all 3 SMA types (P <?.05). We linked these alterations to downregulation of peroxisome proliferator-activated receptor coactivator 1?, the transcriptional activators nuclear respiratory factor 1 and nuclear respiratory factor 2, mitochondrial transcription factor A, and their downstream targets, implying depression of the entire mitochondrial biogenesis. Results of Western blot analysis confirmed the reduced levels of the respiratory chain subunits that included mitochondrially encoded COX1 (47.5%; P =?.004), COX2 (32.4%; P <?.001), COX4 (26.6%; P <?.001), and succinate dehydrogenase complex subunit A (65.8%; P =?.03) as well as the structural outer membrane mitochondrial porin (33.1%; P <?.001). Conversely, the levels of expression of 3 myogenic regulatory factors-muscle-specific myogenic factor 5, myoblast determination 1, and myogenin-were higher in muscles from patients with SMA compared with muscles from age-matched controls (P <?.05). CONCLUSIONS AND RELEVANCE:Our results strongly support the conclusion that an altered regulation of myogenesis and a downregulated mitochondrial biogenesis contribute to pathologic change in the muscle of patients with SMA. Therapeutic strategies should aim at counteracting these changes.

Project description:Genetic therapy has changed the prognosis of hereditary proximal spinal muscular atrophy, although treatment efficacy has been variable. There is a clear need for deeper understanding of underlying causes of muscle weakness and exercise intolerance in patients with this disease to further optimize treatment strategies. Animal models suggest that in addition to motor neuron and associated musculature degeneration, intrinsic abnormalities of muscle itself including mitochondrial dysfunction contribute to the disease aetiology. To test this hypothesis in patients, we conducted the first in vivo clinical investigation of muscle bioenergetics. We recruited 15 patients and 15 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. MRI and 31P magnetic resonance spectroscopy, the modality of choice to interrogate muscle energetics and phenotypic fibre-type makeup, was performed of the proximal arm musculature in combination with fatiguing arm-cycling exercise and blood lactate testing. We derived bioenergetic parameter estimates including: blood lactate, intramuscular pH and inorganic phosphate accumulation during exercise, and muscle dynamic recovery constants. A linear correlation was used to test for associations between muscle morphological and bioenergetic parameters and clinico-functional measures of muscle weakness. MRI showed significant atrophy of triceps but not biceps muscles in patients. Maximal voluntary contraction force normalized to muscle cross-sectional area for both arm muscles was 1.4-fold lower in patients than in controls, indicating altered intrinsic muscle properties other than atrophy contributed to muscle weakness in this cohort. In vivo31P magnetic resonance spectroscopy identified white-to-red remodelling of residual proximal arm musculature in patients on the basis of altered intramuscular inorganic phosphate accumulation during arm-cycling in red versus white and intermediate myofibres. Blood lactate rise during arm-cycling was blunted in patients and correlated with muscle weakness and phenotypic muscle makeup. Post-exercise metabolic recovery was slower in residual intramuscular white myofibres in patients demonstrating mitochondrial ATP synthetic dysfunction in this particular fibre type. This study provides the first in vivo evidence in patients that degeneration of motor neurons and associated musculature causing atrophy and muscle weakness in 5q spinal muscular atrophy type 3 and 4 is aggravated by disproportionate depletion of myofibres that contract fastest and strongest. Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibres provides both a possible clue to understanding the apparent vulnerability of this particular fibre type in 5q spinal muscular atrophy types 3 and 4 as well as a new biomarker and target for therapy.