本研究ではラット生体モデルにバイオイメージング技法を適用し，末梢性疲労 のメカニズムを検討するために，疲労時の微小循環動態および筋細胞代謝動態 の可視化を試み，以下の研究課題を遂行した．
研究課題 1 ：ラット in vivo モデルにおける張力発揮動態
生体内環境下（in vivo）での筋疲労動態観察モデルの確立を目的として，ラッ ト脊柱僧帽筋における異なる収縮刺激負荷に対する発揮張力特性を検討した．
その結果，
0.2-ms
刺激と比べて，4-ms
刺激での連続的な等尺性の強縮負荷時に 顕著な筋疲労が誘発されることが明らかとなった（実験1‐1）
．さらに，この4-ms
刺激を用いた伸張性収縮負荷では，疲労の顕著な等尺性収縮とは異なり，張力発揮が維持されることが示された（実験
1‐2）
．また，実験1
と同様の刺激 プロトコルにより，筋疲労には性差が生じることが示された（実験1‐3）
．研究課題 2 ：筋疲労時の微小血管動態の評価
実験
1
において観察された疲労の差が，血液循環の違いによるものかどうか を明らかにするために，連続的な筋収縮後の末梢血管動態の評価をおこなった．その結果，4-ms の刺激条件では筋収縮直後に細動脈の収縮が筋収縮の頻度依存 で生じ，細動脈の収縮は筋疲労が顕著になるにつれて増大することが明らかに なった（実験
4）
．次に，α-アドレナリン受容体を薬理学的に阻害し，交感神経103
系の筋疲労への関与を検討した．その結果，連続的な筋収縮後に細動脈の血管 収縮作用が亢進する機序は，α1-ならびに
α2-アドレナリン受容体を介したもの
であることが明らかとなった（実験5）
．血管緊張を決定する拡張作用と収縮作 用との動的平衡は，運動の継続に伴って交感神経性の血管収縮作用が優位にな り，その結果として，運動後における血液供給量の低下を招き，筋疲労の回復 が遅延することに関係していることが考えられた．研究課題 3 ：筋疲労時の筋細胞代謝動態の評価
ラット生体モデルに蛍光指示薬を用いたバイオイメージング法を適用し，筋疲 労時の筋細胞代謝動態の評価を，細胞内の
Ca
2+およびpH
動態に焦点を当ててお こなった．実験2
の結果を受け，その要因としてCa
2+の関与を検討するために，バイオイメージング法を用いて，筋細胞内の
Ca
2+動態を評価し，伸張性収縮で は等尺性収縮と比較して顕著なCa
2+の蓄積が生じることが明らかとなった（実 験6）
．さらに，実験3
において観察された疲労の性差における要因を検討し，雄と比較して雌では
Ca
2+の蓄積が生じないことが示され，Ca
2+の蓄積にはエスト ロゲンの関与が低いことが示唆された（実験7）
．筋疲労時の細胞内pH
動態の 評価とその制御機構についての検討においては（実験8）
，筋疲労時おいてもpH
が一定に保たれる傾向を示し，それはMCT
を通じて細胞外へと排出されるため であり，アシドーシスが従来指摘されていたような疲労要因ではないことが示 唆された．本研究によって，血流や細胞膜といった生体恒常性が維持されたモデルを用 いることが，これまでに蓄積された
in vitro
での知見がin vivo
では必ずしも生じ104
ていない可能性が示唆された．今後の課題として，このモデルを更に発展させ ることによって，微小循環動態と疲労に関わる様々なイオン動態，筋の形態学 的特性などを同時に観察することができれば，複雑な疲労メカニズムを生理学 的，形態学的および生化学的視点から複合的に明らかにすることが可能になる と考えられる．
105
謝辞
本稿を終えるにあたり，懇切丁寧な御指導を賜りました 狩野 豊 准教授に深 く御礼申し上げます．本稿の作成に際し，御校閲賜りました電気通信大学 先 進理工学科 丹羽 治樹 教授，中村 整 教授，樫森 与志喜 准教授，白 川 英樹 准教授，長澤 純一 准教授に厚く御礼申し上げます．また，本研 究を遂行するにあたり，親切な御指導を賜りましたカンザス州立大学 David
Poole
氏に心から感謝の意を表します．本実験に際し御協力を頂いた国立循環器病研究センター 曽野部 崇氏ならびに福岡大学 須藤みずき氏をはじめ，狩野 研究室の皆様にも深く心からの感謝を申し上げます．
最後に，学位取得にあたり多大なる支援を賜りました家族に心から感謝いたし ます．
106
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