Immobilization leads to alterations in intracellular phosphagen and creatine transporter content in human skeletal muscle

Abstract

The role of dysregulated intracellular creatine (Cr) metabolism in disuse atrophy is unknown. In this study, skeletal muscle biopsy samples were obtained after 7 days of unilateral leg immobilization (IMMOB) and from the nonimmobilized control limb (CTRL) of 15 healthy men (23.1 ± 3.5 yr). Samples were analyzed for fiber type cross-sectional area (CSA) and creatine transporter (CreaT) at the cell membrane periphery (MEM) or intracellular (INT) areas, via immunofluorescence microscopy. Creatine kinase (CK) and AMP-activated protein kinase (AMPK) were determined via immunoblot. Phosphocreatine (PCr), Cr, and ATP were measured via enzymatic analysis. Body composition and maximal isometric knee extensor strength were assessed before and after disuse. Leg strength and fat-free mass were reduced in IMMOB (~32% and 4%, respectively; P < 0.01 for both). Type II fiber CSA was smaller (~12%; P = 0.028) and intramuscular PCr lower (~13%; P = 0.015) in IMMOB vs. CTRL. CreaT protein was greater in type I fibers in both limbs ( P < 0.01). CreaT was greater in IMMOB vs. CTRL ( P < 0.01) and inversely associated with PCr concentration in both limbs ( P < 0.05). MEM CreaT was greater than INT CreaT in type I and II fibers of both limbs (~14% for both; P < 0.01 for both). Type I fiber CreaT tended to be greater in IMMOB vs. CTRL ( P = 0.074). CK was greater and phospho-to-total AMPKThr172 tended to be greater, in IMMOB vs. CTRL ( P = 0.013 and 0.051, respectively). These findings suggest that modulation of intracellular Cr metabolism is an adaptive response to immobilization in young healthy skeletal muscle.

Creatine for Exercise and Sports Performance, with Recovery Considerations for Healthy Populations

“…Previous research has identified reductions in intracellular phosphagen and glycogen content following muscle disuse [135]. More recently, it was discovered that periods of muscle disuse also resulted in alterations in intracellular phosphagen and creatine transporter content in human skeletal muscle, demonstrating how the cell adapts to the aforementioned metabolic disruptions in cellular energy turnover [136]. These alterations in intracellular phosphate and transporter protein content, coupled with mitochondrial-mediated apoptosis, highlight a rationale for the potential therapeutic benefit of creatine supplementation to attenuate reductions in phosphagen levels associated with muscle disuse.…”

Gene Ontology (GO)-Driven Inference of Candidate Proteomic Markers Associated with Muscle Atrophy Conditions

“…In contrast to the complexity of interacting pathways involved in cancer-related cachexia, the key changes associated with sarcopenia included the downregulation of pathways related to energy metabolism, namely the phosphagen metabolic system, gluconeogenesis pathway, and the proton-transporting ATP synthase activity, among others ( Figure 4 A). In a study investigating the role of dysregulated intracellular creatine metabolism in disuse muscle, Luo et al demonstrated that seven days of unilateral limb immobilization resulted in greater intracellular creatinine transporter and reduced phosphocreatine content when compared with the non-immobilized control limb in a cohort of 15 healthy men; they hypothesized that the lower intramuscular phosphocreatine content observed might be explained by the significantly lower fast-twitch fiber cross-sectional area compared with the control biopsies from the non-immobilized limb [ 65 ]. Sarcopenia and aging have been associated with the preferential atrophy of fast-twitch fibers and a glycolytic-to-oxidative metabolic shift [ 39 , 66 ].…”

Metabolic Pathways and Ion Channels Involved in Skeletal Muscle Atrophy: A Starting Point for Potential Therapeutic Strategies

“…Creatine is an energetic compound able to induce the recycling of adenosine triphosphate (ATP) in skeletal muscle tissue. It can have a beneficial role during immobilization-induced muscle disuse in humans [ 179 , 180 ]. Alongside amino acids, vitamins also play an essential role in the prevention of muscle atrophy characterized by an increase in oxidative stress and a decrease in the production of endogenous antioxidant species.…”