Elevated Tumor Necrosis Factor-α in Skeletal Muscle After Stroke

Abstract

Background and Purpose-Tumor necrosis factor-␣ (TNF-␣), an inflammatory cytokine negligibly expressed in normal muscle, is elevated in selected metabolic conditions characterized by muscle wasting and insulin resistance. Inflammation is fundamental to stroke pathogenesis. Stroke patients have gross muscular atrophy and high prevalence of diabetes and insulin resistance. Yet, no previous studies examined TNF-␣ expression in hemiparetic skeletal muscle. This study investigates whether TNF-␣ mRNA levels are elevated in paretic compared with nonparetic leg muscles of chronic ischemic stroke patients and age-matched controls. Method-Total RNA extracted from bilateral vastus lateralis muscle biopsies from nϭ20 hemiparetic stroke patients and nϭ9 healthy controls was reverse transcribed to cDNA, then TNF-␣ transcripts were amplified by real-time quantitative polymerase chain reaction. TNF-␣ mRNA concentrations were normalized against acidic ribosomal phosphoprotein, housekeeping gene. Results-TNF-␣ mRNA levels were 2.8-fold higher in paretic compared with control leg muscle (6.28Ϯ1.86 versus 2.28Ϯ0.67; PϽ0.03) and 1.6-fold higher in nonparetic leg (3.71Ϯ1.02; PϽ0.11) compared with controls. There was a trend for higher TNF-␣ mRNA in paretic compared with nonparetic leg. Key Words: inflammation Ⅲ insulin Ⅲ stroke Ⅲ tumor necrosis factor I nflammation is a fundamental pathogenic mechanism in atherosclerosis and stroke. 1,2 Elevated inflammatory markers predict risk for incident and recurrent stroke. 3,4 Tumor necrosis factor-␣ (TNF-␣), a pivotal cytokine, upregulates systemic inflammatory markers, mediates insulin resistance, and increases cardiovascular risk. 2,5 Associations between type 2 diabetes and muscle TNF-␣ overexpression are strong and are attributed to TNF-␣ actions on muscle insulin signaling. 6 Stroke survivors have a 70% prevalence of diabetes and insulin resistance. 9 Despite evidence linking inflammation with stroke risk, diabetes, and insulin resistance, the tissue source(s) for cytokines have not been systematically investigated in the stroke population. Conclusions-FindingsStroke is a leading cause of chronic disability, possibly attributable to secondary abnormalities in skeletal muscle. 8,10 We report gross muscular atrophy and phenotype shift in hemiparetic thigh that independently predict poor fitness levels and gait severity after stroke. 8,10,11 Although skeletal muscle TNF-␣ can mediate muscular wasting and physical frailty in advancing age, 7 no previous studies investigated TNF-␣ expression in hemiparetic muscle after stroke. The hypothesis of this cross-sectional study is that TNF-␣ mRNA expression is elevated in paretic compared with nonparetic leg muscle after stroke. Because stroke may constitute a systemic biological process, muscle biopsies from healthy age-matched sedentary community reference controls are examined to determine whether hemiparetic leg muscle TNF-␣ is abnormal. Patients and MethodsMen and women Ն45 years of age with hemiparetic gait after remote (Ͼ6 months) ischemic str...

Human genome comparison of paretic and nonparetic vastus lateralis muscle in patients with hemiparetic stroke

“…We previously reported that TNF-α levels were significantly elevated in the VL muscles of the paretic compared with the nonparetic leg after stroke [14]. In the present study, we report elevated gene expression of a disintegrin and metalloprotease (ADAM) in the paretic leg muscle after stroke.…”

“…The loss of slow-twitch fibers that take up glucose in response to insulin is relevant to the high prevalence of insulin resistance in stroke survivors [13]. In addition, expression of tumor necrosis factor alpha (TNF-α), an inflammatory cytokine, is elevated in the hemiparetic leg muscle compared with the nonparetic leg muscle [14]. Whether broader inflammatory pathway activation is present with subsequent downstream impact on muscle cell cycle, protein synthesis, or metabolic function is unknown.…”

“…The vastus lateralis (VL) muscle was chosen since all our subjects with hemiparetic stroke have quadriceps weakness and the majority have evidence of spasticity of knee extension. Furthermore, the quadriceps muscle is traditionally examined in studies of aging, diabetes, and exercise interventions [14][15]. This study used Affymetrix deoxyribonucleic acid (DNA) microarray analysis to investigate global gene expression changes underlying the biological changes of muscle structure and metabolic function in paretic and nonparetic VL muscle from subjects with chronic stroke.…”

Loss of muscle mass: Current developments in cachexia and sarcopenia focused on biomarkers and treatment

“…58,59 It has been shown that elevated volumes of TNF-α are responsible for muscle loss and that plasma concentrations of the enzyme visfatin were significantly elevated in patients after ischemic stroke. 60,61 For that, investigations to changes of inflammation parameters and its relation to body composition, insulin sensitivity, and patient's survival will be made as well. 55 …”

Task-oriented treadmill exercise training in chronic hemiparetic stroke

“…Specifically, a deficit severity-dependent shift toward a fast-twitch muscle molecular phenotype in the paretic leg results in a more fatigable muscle fiber type that is more insulin resistant, which may contribute to the high incidence of IGT in this population [31][32][33]. Furthermore, nearly threefold elevated levels of tumor necrosis factor-α (TNF-α) messenger RNA are reported in hemiparetic quadriceps muscle from patients with stroke compared with those from nonparetic legs and nonstroke control subjects [34]. Elevated TNF-α levels in skeletal muscle tissue are strongly linked to muscular wasting and insulin resistance in T2DM and advancing age and may contribute to the structural and metabolic abnormalities in hemiparetic skeletal muscle after stroke [35][36][37][38].…”