悪液質の機能障害と代謝順応

非小細胞肺がん悪液質患者の機能障害と代謝順応に関する研究を紹介します。

Anne-Marie C. Dingemans, et al: Functional impairment and distinct metabolic adaptations in skeletal muscle of pre-cachectic and cachectic patients with non-small cell lung cancer

非小細胞肺がん患者では、前悪液質のような発症後早期でも運動能力が低下しているという報告があります。そこで悪液質患者（悪液質16人、前悪液質10人）と健常者22人の身体機能、筋肉生検（大腿四頭筋）、酸化的代謝の調節因子・酵素を評価しました。

結果です。骨格筋の筋肉量減少は悪液質のみ認め、前悪液質では認めませんでしたが、身体機能は悪液質、前悪液質とも低下していました。筋生検では遅筋から速筋への有意な移行を認めました。酸化的代謝の調節因子は悪液質、前悪液質とも低下し、酸化的代謝の酵素は悪液質のみ低下していました。

悪液質・前悪液質では、筋線維の遅筋から速筋への移行や酸化的代謝の変化によって、運動耐容能低下を認める可能性があるという結論です。

遅筋から速筋への移行は、廃用性筋萎縮でも生じます。一方、原発性サルコペニア（加齢）単独での場合、速筋から遅筋に移行します。前悪液質・悪液質の患者に廃用症候群を合併すると、より遅筋から速筋への移行が進み、易疲労性が目立つ可能性があります。前悪液質・悪液質では特に廃用予防が重要かつ有効かもしれません。

Background: A recent study demonstrated that exercise capacity is already decreased in patients with early stages of non-small cell lung cancer (NSCLC) cachexia, i.e. pre-cachexia. As physical performance is an important determinant of quality of life and mortality, we further focused on the molecular basis of this observation.

Aim: This study aims to investigate whether histochemical and metabolic properties of skeletal muscle are altered in pre-cachectic and cachectic patients with NSCLC.

Methods: In this prospective study, 22 healthy controls and 16 cachectic and 10 pre-cachectic patients with NSCLC were studied. Physical performance was assessed using quality of life (QLQ-C30) and physical activity (SF-20) questionnaires. Quadriceps muscle biopsies were analyzed by immunohistochemistry to distinguish muscle fibers containing type I (oxidative), type IIa (mixed) or type IIx (glycolytic) myosin heavy chain isoforms. Furthermore, expression and activity of an important regulator (PGC1alpha) and enzymes (citrate synthase and 3-Hydroxyacyl-CoA dehydrogenase) of oxidative metabolism were assessed.

Results: Although skeletal muscle mass was only significantly decreased in patients with cachexia (p < 0.001), both patients groups showed decreased physical performance (p < 0.001). Interestingly, both patients with pre-cachexia and cachexia demonstrated a fiber type I to >II shift compared with healthy controls. While pre-cachectic patients showed a higher percentage of type IIx (p = 0.015), cachectic patients showed a higher percentage of type IIa (p = 0.036) fibers. mRNA expression of PGC1alpha was decreased in both patients groups and decreased activity of oxidative enzymes was observed in muscle of patients with cachexia.

Conclusions: The shift from types I to II fibers and alterations in oxidative metabolism observed in both patients with pre-cachexia and cachexia may lie at the basis of exercise intolerance in these patient groups. The relative shift to type IIa or IIx fibers in cachexia and pre-cachexia, respectively, implicates that metabolic adaptations are distinct in successive stages of cachexia.