Physical inactivity induced neuromuscular impairment: comparison of younger and older adults

Physical inactivity (PI) is independent and already a 2nd mortality risk factor, causing >5 million deaths per year. It can be considered a pandemic because it reduces exercise tolerance and dramatically increases the risk of disease. The main phenomena occur at the level of muscle (loss of mass and strength), nervous system (impaired central and peripheral motor control), and metabolism (impaired oxidative metabolism and insulin resistance). Most studies focused only on muscle, on young people and few also on older people. Few studies addressed the interactions between muscles and neural control through sensorimotor loops and neuromuscular junctions (NMJ) that lead to exercise intolerance and whole-body metabolic impairments. PI affects all age groups, and little is known about the effects of PI on function in middle-aged adults (55-65). In addition, the recent outbreak of COVID -19 has triggered PI in millions of people of all ages worldwide and highlighted its deleterious consequences. Project activities will focus on neuromuscular and metabolic deterioration during PI and recovery thereafter. The effects of PI will be studied using highly controlled bed rest (BR), which is considered the gold standard for studying PI, in 10 younger (18-30 years) and 10 older (55-65 years) male adults for 21 and 10 days, respectively. In addition, 20 younger and 20 older adult participants (of either sex) will undergo two rounds of lifestyle intervention - 15 days of step reduction (SR) to 3,500 and 1,500 daily steps, respectively, to determine the minimum daily steps needed to maintain neuromuscular health. In the BR and SR studies, participants will also complete 21 days of retraining. Because short-term (7-15 days) offloading is common in both the young and elderly, in bedridden patients after injury or surgery, and in critically ill, investigating the possible determinants of disproportionate reductions in muscle function compared with reductions in muscle size and structure is of great importance. Although disuse is a major project goal, we will equally important study recovery part too. We will address 3 objectives using 10 interrelated tasks in young and middle-aged adults in PI models of bed rest (BR) and step reduction (SR). Aim 1: define the impairment of neuromuscular control Task 1: muscle volume, architecture, contractibility, strength, and power Task 2: muscle fiber size, force, tension, velocity, extracellular matrix with cytoskeleton and MHC composition Task 3: supraspinal and spinal excitability Task 4: neuromuscular activation patterns and spinal maps Task 5: motor unit behavior and NMJ function Aim 2: define the NMJ alterations and their functional role Task 6: establish the occurrence and extent of NMJ alteration Task 7: define the relationship between NMJ alterations and integrity of muscle structure and function Aim 3: define metabolic impairment: energy and glucose metabolism Task 8: define metabolic impairment at muscle and whole-body level Task 9: investigate insulin resistance & reactive oxygen species role Task 10: define the minimum level of activity required for preventing neuromuscular and metabolic alterations The strength of the project relies on: (i) a scientific team covering a broad range of expertise on the neuromuscular system, from molecular to integrative and clinical research; (ii) the analysis of 2 age groups; (iii) the focus on disuse and retraining; (iv) a broad range of simultaneous in vivo and molecular analyses on the same participants; (v) the analysis of the early onset and time course of the phenomena; (vi) the use of human models of great public health importance (e.g., BR, SR). Ethical issues are very important and will be considered with great importance: participants’ recovery; invasive procedures and medical monitoring in the hospital; prevention of major deterioration and more reliable recovery in older adults through shorter BR and twice as long retraining compared to BR.