Abstract-The extent and mechanism of the cardiac benefit of early exercise training following myocardial infarction (MI) is incompletely understood, but may involve blunting of abnormalities in Ca 2ϩ -handling and myofilament function. Consequently, we investigated the effects of 8-weeks of voluntary exercise, started early after a large MI, on left ventricular (LV) remodeling and dysfunction in the mouse. Exercise had no effect on survival, MI size or LV dimensions, but improved LV fractional shortening from 8Ϯ1 to 12Ϯ1%, and LVdP/dt P30 from 5295Ϯ207 to 5794Ϯ207 mm Hg/s (both PϽ0.05), and reduced pulmonary congestion. These global effects of exercise were associated with normalization of the MI-induced increase in myofilament Ca 2ϩ -sensitivity (⌬pCa 50 ϭ0.037). This effect of exercise was PKA-mediated and likely because of improved ␤ 1 -adrenergic signaling, as suggested by the increased ␤ 1 -adrenoceptor protein (48%) and cAMP levels (36%; all PϽ0.05). Exercise prevented the MI-induced decreased maximum force generating capacity of skinned cardiomyocytes (F max increased from 14.3Ϯ0.7 to 18.3Ϯ0.8 kN/m 2 PϽ0.05), which was associated with enhanced shortening of unloaded intact cardiomyocytes (from 4.1Ϯ0.3 to 7.0Ϯ0.6%; PϽ0.05). Furthermore, exercise reduced diastolic Ca 2ϩ -concentrations (by ϳ30%, PϽ0.05) despite the unchanged SERCA2a and PLB expression and PLB phosphorylation status. Importantly, exercise had no effect on Ca 2ϩ -transient amplitude, indicating that the improved LV and cardiomyocyte shortening were principally because of improved myofilament function. In conclusion, early exercise in mice after a large MI has no effect on LV remodeling, but attenuates global LV dysfunction. The latter can be explained by the exercise-induced improvement of myofilament function. (Circ Res. 2007;100:1079-1088.)Key Words: cardiac function Ⅲ cardiomyocytes Ⅲ exercise training Ⅲ heart failure L eft ventricular (LV) remodeling after myocardial infarction (MI) is a compensatory mechanism that serves to restore LV pump function. Despite the apparent appropriateness of LV remodeling to maintain cardiac pump function early after MI, remodeling is an independent risk factor for the development of congestive heart failure. 1 The mechanism underlying the progression from LV remodeling to overt heart failure remains incompletely understood, but recent evidence indicates that abnormalities in myofilament function and Ca 2ϩ -handling contribute to the LV dysfunction in the porcine heart, early after MI. 2 In contrast to pathological LV remodeling after MI, LV remodeling produced by regular dynamic exercise is associated with a decreased risk for coronary artery disease and heart failure. 3 Exercise training is associated with an increased myocardial perfusion capacity and with normal or even increased contractile function in the normal heart. 4,5 There is also clinical evidence that exercise after MI has a beneficial effect on disease progression and survival. 6,7 For example, physical conditioning in patients with L...

Mitochondrial complex I deficiency is the most common oxidative phosphorylation defect. Mutations have been detected in mitochondrial and nuclear genes, but the genetics of many patients remain unresolved and new genes are probably involved. In a consanguineous family, patients presented easy fatigability, exercise intolerance and lactic acidosis in blood from early childhood. In muscle, subsarcolemmal mitochondrial proliferation and a severe complex I deficiency were observed. Exercise intolerance and complex I activity was improved by a supplement of riboflavin at high dosage. Homozygosity mapping revealed a candidate region on chromosome three containing six mitochondria-related genes. Four genes were screened for mutations and a homozygous substitution was identified in ACAD9 (c.1594 C>T), changing the highly conserved arginine-532 into tryptophan. This mutation was absent in 188 ethnically matched controls. Protein modelling suggested a functional effect due to the loss of a stabilizing hydrogen bond in an α-helix and a local flexibility change. To test whether the ACAD9 mutation caused the complex I deficiency, we transduced fibroblasts of patients with wild-type and mutant ACAD9. Wild-type, but not mutant, ACAD9 restored complex I activity. An unrelated patient with the same phenotype was compound heterozygous for c.380 G>A and c.1405 C>T, changing arginine-127 into glutamine and arginine-469 into tryptophan, respectively. These amino acids were highly conserved and the substitutions were not present in controls, making them very probably pathogenic. Our data support a new function for ACAD9 in complex I function, making this gene an important new candidate for patients with complex I deficiency, which could be improved by riboflavin treatment.

Leigh syndrome is an early onset, often fatal progressive neurodegenerative disorder caused by mutations in the mitochondrial or nuclear DNA. Until now, mutations in more than 35 genes have been reported to cause Leigh syndrome, indicating an extreme genetic heterogeneity for this disorder, but still only explaining part of the cases. The possibility of whole exome sequencing enables not only mutation detection in known candidate genes, but also the identification of new genes associated with Leigh syndrome in small families and isolated cases. Exome sequencing was combined with homozygosity mapping to identify the genetic defect in a Moroccan family with fatal Leigh syndrome in early childhood and specific magnetic resonance imaging abnormalities in the brain. We detected a homozygous nonsense mutation (c.20C>A; p.Ser7Ter) in the thiamine transporter SLC19A3. In vivo overexpression of wild-type SLC19A3 showed an increased thiamine uptake, whereas overexpression of mutant SLC19A3 did not, confirming that the mutation results in an absent or non-functional protein. Seventeen additional patients with Leigh syndrome were screened for mutations in SLC19A3 using conventional Sanger sequencing. Two unrelated patients, both from Moroccan origin and one from consanguineous parents, were homozygous for the same p.Ser7Ter mutation. One of these patients showed the same MRI abnormalities as the patients from the first family. Strikingly, patients receiving thiamine had an improved life-expectancy. One patient in the third family deteriorated upon interruption of the thiamine treatment and recovered after reinitiating. Although unrelated, all patients came from the province Al Hoceima in Northern Morocco. Based on the recombination events the mutation was estimated to have occurred 1250-1750 years ago. Our data shows that SLC19A3 is a new candidate for mutation screening in patients with Leigh syndrome, who might benefit from high doses of thiamine and/or biotin. Especially, Moroccan patients with Leigh syndrome should be tested for the c.20C>A founder mutation in SLC19A3.

The phenotype associated with ECHS1 mutations might be milder than reported earlier, compatible with prolonged survival, and also includes isolated paroxysmal exercise-induced dystonia. ECHS1 screening should be considered in patients with otherwise unexplained paroxysmal exercise-induced dystonia, in addition to those with Leigh and Leigh-like syndromes. Diet regimens and detoxifying agents represent potential therapeutic strategies. © 2016 International Parkinson and Movement Disorder Society.