Cardiovascular disease, psychiatric diagnosis and sex differences in the multistep hypothesis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) risk increases with age, and a linear log-incidence and log-age relationship is interpreted to suggest that five to six factors are involved in disease onset. The factors remain unidentified, except that fewer steps are predicted for those carrying a known ALS-causing mutation. METHODS: Men with a psychiatric disorder or cardiovascular disease (CVD) diagnosis have an increased relative risk of ALS. Using the Danish population registries and ALS diagnosis years 1980 to 2017, we tested whether these factors would decrease the predicted steps to disease. RESULTS: Consistent with previous reports, we find a linear log-incidence and log-age ALS-onset relationship (n = 4385, regression coefficient b = 4.6, 95% confidence interval [CI]: 4.3-4.9, R2  = 0.99). This did not differ when considering ALS cases with a prior psychiatric diagnosis (n = 391, b = 4.6, 95% CI: 4.0-5.1) Surprisingly, it was higher (+1.5 steps, P = 2.3 × 10-5 ) for those with a prior CVD diagnosis (n = 901, b = 6.1, 95% CI: 5.4-6.8). To control for competing risk of death, a test to investigate if this effect was maintained in those with CVD in the population demonstrated an increased baseline risk and fewer steps to disease (b = 1.8, 95% CI: 1.2-2.3, P = 4.6 × 10-21 ), which consistent with a positive association of CVD and ALS. Assessing sex differences, our data and meta-analyses (n = 22 495) support half a step fewer for men (-0.4, 95% CI: ±0.24, P = 0.00031) without support for contributing differences explained by menopause. CONCLUSIONS: Any factor associated with ALS disease onset may be relevant for understanding disease pathogenesis and/or counselling. Modelling disease incidence with age demonstrates some insight into relevant risk factors; however, the outcome can differ if competing risks are considered.

α-Actinin-3 deficiency alters muscle adaptation in response to denervation and immobilization.

Homozygosity for a common null polymorphism (R577X) in the ACTN3 gene results in the absence of the fast fibre-specific protein, α-actinin-3 in ∼16% of humans worldwide. α-Actinin-3 deficiency is detrimental to optimal sprint performance and benefits endurance performance in elite athletes. In the general population, α-actinin-3 deficiency is associated with reduced muscle mass, strength and fast muscle fibre area, and poorer muscle function with age. The Actn3 knock-out (KO) mouse model mimics the human phenotype, with fast fibres showing a shift towards slow/oxidative metabolism without a change in myosin heavy chain (MyHC) isoform. We have recently shown that these changes are attributable to increased activity of the calcineurin-dependent signalling pathway in α-actinin-3 deficient muscle, resulting in enhanced response to exercise training. This led us to hypothesize that the Actn3 genotype influences muscle adaptation to disuse, irrespective of neural innervation. Separate cohorts of KO and wild-type mice underwent 2 weeks immobilization and 2 and 8 weeks of denervation. Absence of α-actinin-3 resulted in reduced atrophic response and altered adaptation to disuse, as measured by a change in MyHC isoform. KO mice had a lower threshold to switch from the predominantly fast to a slower muscle phenotype (in response to immobilization) and a higher threshold to switch to a faster muscle phenotype (in response to denervation). We propose that this change is mediated through baseline alterations in the calcineurin signalling pathway of Actn3 KO muscle. Our findings have important implications for understanding individual responses to muscle disuse/disease and training in the general population.