Abstract
Declining muscle mass and function is one of the main drivers of loss of independence in the elderly. Sarcopenia is associated with numerous cellular and endocrine perturbations, and it remains challenging to identify those changes that play a causal role and could serve as targets for therapeutic intervention. In this study, we uncovered a remarkable differential susceptibility of certain muscles to age-related decline. Aging rats specifically lose muscle mass and function in the hindlimbs, but not in the forelimbs. By performing a comprehensive comparative analysis of these muscles, we demonstrate that regional susceptibility to sarcopenia is dependent on neuromuscular junction fragmentation, loss of motoneuron innervation, and reduced excitability. Remarkably, muscle loss in elderly humans also differs in vastus lateralis and tibialis anterior muscles in direct relation to neuromuscular dysfunction. By comparing gene expression in susceptible and non-susceptible muscles, we identified a specific transcriptomic signature of neuromuscular impairment. Importantly, differential molecular profiling of the associated peripheral nerves revealed fundamental changes in cholesterol biosynthetic pathways. Altogether our results provide compelling evidence that susceptibility to sarcopenia is tightly linked to neuromuscular decline in rats and humans, and identify dysregulation of sterol metabolism in the peripheral nervous system as an early event in this process.
Highlights
Skeletal muscle mass and function decline gradually with age and become debilitating in 5-20% of elderly in populations aged over 65 [1,2,3]
One of the challenges to maintain mobility and physical function in elderly arises from the overlap of a wide range of molecular, cellular, endocrine and nutritional perturbations occurring with age
The compound muscle action potential (CMAP) is a clinical assessment of neuromuscular function that is widely used to examine a range of motoneuron and muscle diseases because it indicates the sum of excitable tissue, it does not necessarily indicate the numbers of motoneurons per se
Summary
Skeletal muscle mass and function decline gradually with age and become debilitating in 5-20% of elderly in populations aged over 65 [1,2,3]. This syndrome is commonly referred to as sarcopenia or physical frailty [4], and represents a major risk factor for falls, loss of independence in activities of daily living, nursing home admissions and, mortality [1]. Sarcopenia is caused by multi-factorial endocrine and cellular processes that lead to defects in the contractile function of skeletal muscle. Motor innervation of skeletal muscle is propagated via motoneurons which elongate from the spinal cord along peripheral nerves to innervate highly specialized cholinergic synapses www.impactaging.com
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