Can muscle protein metabolism be specifically targeted by exercise training in COPD?

Abstract

Patients with stable chronic obstructive pulmonary disease (COPD) frequently exhibit unintentional accentuated peripheral muscle loss and dysfunction. Skeletal muscle mass in these patients is a strong independent predictor of morbidity and mortality. Factors including protein anabolism/catabolism imbalance, hypoxia, physical inactivity, inflammation, and oxidative stress are involved in the initiation and progression of muscle wasting in these patients. Exercise training remains the most powerful intervention for reversing, in part, muscle wasting in COPD. Independently of the status of systemic or local muscle inflammation, rehabilitative exercise training induces up-regulation of key factors governing skeletal muscle hypertrophy and regeneration. However, COPD patients presenting similar degrees of lung dysfunction do not respond alike to a given rehabilitative exercise stimulus. In addition, a proportion of patients experience limited clinical outcomes, even when exercise training has been adequately performed. Consistently, several reports provide evidence that the muscles of COPD patients present training-induced myogenic activity limitation as exercise training induces a limited number of differentially expressed genes, which are mostly associated with protein degradation. This review summarises the nature of muscle adaptations induced by exercise training, promoted both by changes in the expression of contractile proteins and their function typically controlled by intracellular signalling and transcriptional responses. Rehabilitative exercise training in COPD patients stimulates skeletal muscle mechanosensitive signalling pathways for protein accretion and its regulation during muscle contraction. Exercise training also induces synthesis of myogenic proteins by which COPD skeletal muscle promotes hypertrophy leading to fusion of myogenic cells to the myofiber. Understanding of the biological mechanisms that regulate exercise training-induced muscle growth and regeneration is necessary for implementing therapeutic strategies specifically targeting myogenesis and hypertrophy in these patients.

Keywords: Chronic obstructive pulmonary disease (COPD); anabolism; exercise; hypertrophy; muscle wasting; myogenesis; protein synthesis.

Figure 1

COPD skeletal muscle adaptations to various modalities of exercise training. Exercise training is a powerful stimulus producing hypertrophy and regeneration of muscle by increased protein metabolism and fusion of satellite cells to existent myofiber. Endurance- and resistance-based exercise training programmes are characterised as stimuli capable for increasing oxidative capacity and hypertrophy, respectively, whereas high intensity interval training is capable of increasing both oxidative capacity and hypertrophy. Skeletal muscle adaptations observed from combined endurance/resistance as well as high intensity interval training reflect a wider range of stimuli. [The Figure has been inspired by Robinson et al. (21) and modified based on presented theory]. COPD, chronic obstructive pulmonary disease.

Figure 2

Diagram of the major signalling pathways involved in the control of skeletal muscle hypertrophy and mitochondrial biogenesis. Voluntary exercise training activates kinases/phosphatases to mediate a specific exercise-induced signal. The cross talk among the numerous signalling pathways activated and the multiple site regulation produces a high sensitive and complex transduction network. Activation of AMPK by aerobic/endurance exercise training enhances mitochondrial biogenesis partly by directly phosphorylating and activating PGC-1α. Resistance training is a potent stimulus for the increase in skeletal muscle mass. Activation of FAK through integrins leads to the inhibition of TSC, thereby permitting activation of mTOR. In addition, hypertrophy is promoted by activation of IGF-1 activating PI3K/Akt/mTOR signaling pathway that leads to hypertrophy. AMPK, AMP-activated protein kinase; PGC-1α, PPAR-γ coactivator 1α; FAK, focal adhesion kinase; TSC, tuberous sclerosis complex; mTOR, mammalian target of rapamycin; IGF-1, insulin-like growth factor 1; PI3K, phosphatidylinositide 3-kinases.