Altered signaling for mitochondrial and myofibrillar biogenesis in skeletal muscles of multiple sclerosis patients

Abstract

Patients with MS (pwMS) experience muscle weakness and lowered muscle oxidative capacity. To explore the etiology for the development of such muscle phenotype we studied skeletal muscle AMP-activated protein kinase (phospho-AMPKα, governing mitochondrial biogenesis) and mammalian target of rapamycin (phospho-mTOR, governing myofibrillar biogenesis) phosphorylation in pwMS. After assessment of body composition, muscle strength, exercise tolerance and muscle fiber type, muscle phospho-AMPKα and phosphomTOR was assessed in 14 pwMS and 10 healthy controls (part 1). Next, an endurance exercise bout was executed by 9 pwMS and 7 healthy subjects, with assessment of changes in muscle phospho-AMPKα and phospho-mTOR (part 2). Elevated basal muscle phosphoAMPKα and phospho-mTOR was present in MS (p<0.01) and independently related to MS. Correlations between muscle phospho-AMPKα or phospho-mTOR and whole-body fat mass, peak oxygen uptake and expanded disability status scale (p<0.05) were found. After endurance exercise muscle phospho-AMPKα and phospho-mTOR remained elevated in pwMS (p<0.01). Muscle signaling cascades for mitochondrial and myofibrillar biogenesis are altered in MS and related to impairment and disability level. These findings indicate a link between muscle signaling cascades and level of disability/impairment, and thus may open a new area for the development of novel therapies for peripheral muscle impairment in MS.