Abstract
BackgroundDisuse muscle atrophy is a major comorbidity in patients with chronic diseases including cancer. We sought to explore the kinetics of molecular mechanisms shown to be involved in muscle mass loss throughout time in a mouse model of disuse muscle atrophy and recovery following immobilization.MethodsBody and muscle weights, grip strength, muscle phenotype (fiber type composition and morphometry and muscle structural alterations), proteolysis, contractile proteins, systemic troponin I, and mitochondrial content were assessed in gastrocnemius of mice exposed to periods (1, 2, 3, 7, 15 and 30 days) of non-invasive hindlimb immobilization (plastic splint, I cohorts) and in those exposed to reloading for different time-points (1, 3, 7, 15, and 30 days, R cohorts) following a seven-day period of immobilization. Groups of control animals were also used.ResultsCompared to non-exposed controls, muscle weight, limb strength, slow- and fast-twitch cross-sectional areas, mtDNA/nDNA, and myosin content were decreased in mice of I cohorts, whereas tyrosine release, ubiquitin-proteasome activity, muscle injury and systemic troponin I levels were increased. Gastrocnemius reloading following splint removal improved muscle mass loss, strength, fiber atrophy, injury, myosin content, and mtDNA/nDNA, while reducing ubiquitin-proteasome activity and proteolysis.ConclusionsA consistent program of molecular and cellular events leading to reduced gastrocnemius muscle mass and mitochondrial content and reduced strength, enhanced proteolysis, and injury, was seen in this non-invasive mouse model of disuse muscle atrophy. Unloading of the muscle following removal of the splint significantly improved the alterations seen during unloading, characterized by a specific kinetic profile of molecular events involved in muscle regeneration. These findings have implications in patients with chronic diseases including cancer in whom physical activity may be severely compromised.
Highlights
Muscle dysfunction and wasting are common comorbidities of chronic diseases such as cancer, critical illness, chronic heart failure and respiratory conditions, e.g. chronic obstructive pulmonary disease (COPD) [1,2,3,4,5]
Compared to non-exposed controls, muscle weight, limb strength, slow- and fast-twitch cross-sectional areas, Mitochondrial DNA (mtDNA)/nuclear DNA (nDNA), and myosin content were decreased in mice of I cohorts, whereas tyrosine release, ubiquitin-proteasome activity, muscle injury and systemic troponin I levels were increased
A consistent program of molecular and cellular events leading to reduced gastrocnemius muscle mass and mitochondrial content and reduced strength, enhanced proteolysis, and injury, was seen in this non-invasive mouse model of disuse muscle atrophy
Summary
Muscle dysfunction and wasting are common comorbidities of chronic diseases such as cancer, critical illness, chronic heart failure and respiratory conditions, e.g. chronic obstructive pulmonary disease (COPD) [1,2,3,4,5]. Malnutrition and other metabolic disorders and aging may aggravate chronic disease-associated muscle wasting in patients. These are serious comorbidities that need to be frequently overcome in actual clinical settings. The most important players involved in the pathophysiology of muscle mass loss associated with respiratory and cardiac disorders and cancer are systemic inflammation, hypoxia, malnutrition, drugs, cigarette smoking, and deconditioning [3,4,6]. Disuse muscle atrophy is a major comorbidity in patients with chronic diseases including cancer. We sought to explore the kinetics of molecular mechanisms shown to be involved in muscle mass loss throughout time in a mouse model of disuse muscle atrophy and recovery following immobilization
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