Mitochondrial maintenance via autophagy contributes to functional skeletal muscle regeneration and remodeling.
The primary objective of this study was to determine whether alterations in mitochondria affect recovery of skeletal muscle strength and mitochondrial enzyme activity following myotoxic injury. 3-Methyladenine (3-MA) was administered daily (15 mg/kg) to blunt autophagy, and the creatine analog guanidionpropionic acid (β-GPA) was administered daily (1% in chow) to enhance oxidative capacity. Male C57BL/6 mice were randomly assigned to nontreatment (Con, n = 6), 3-MA-treated (n = 6), and β-GPA-treated (n = 8) groups for 10 wk. Mice were euthanized at 14 days after myotoxic injury for assessment of mitochondrial remodeling during regeneration and its association with the recovery of muscle strength. Expression of several autophagy-related proteins, e.g., phosphorylated Ulk1 (∼2- to 4-fold, P < 0.049) was greater in injured than uninjured muscles, indicating a relationship between muscle regeneration/remodeling and autophagy. By 14 days postinjury, recovery of muscle strength (18% less, P = 0.03) and mitochondrial enzyme (e.g., citrate synthase) activity (22% less, P = 0.049) were significantly lower in 3-MA-treated than Con mice, suggesting that the autophagy process plays an important role during muscle regeneration. In contrast, muscle regeneration was nearly complete in β-GPA-treated mice, i.e., muscle strength recovered to 93% of baseline vs. 78% for Con mice. Remarkably, 14 days allowed sufficient time for a near-complete recovery of mitochondrial function in β-GPA-treated mice (e.g., no difference in citrate synthase activity between injured and uninjured, P = 0.49), indicating a robust mitochondrial remodeling process during muscle regeneration. In conclusion, autophagy is likely activated following muscle injury and appears to play an important role in functional muscle regeneration.
Department of Kinesiology, University of Georgia, Athens, Georgia;
Anna S
AS
Nichenko
Department of Kinesiology, University of Georgia, Athens, Georgia;
W Michael
WM
Southern
Department of Kinesiology, University of Georgia, Athens, Georgia; Regenerative Bioscience Center, University of Georgia, Athens, Georgia;
Mark
M
Atuan
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia; and.
Junna
J
Luan
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia; and.
Kristen B
KB
Peissig
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia; and.
Steven J
SJ
Foltz
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia; and.
Aaron M
AM
Beedle
Department of Physical Therapy, Byrdine F. Lewis School of Nursing and Health Professions, Georgia State University, Atlanta, Georgia.
Gordon L
GL
Warren
Department of Kinesiology, University of Georgia, Athens, Georgia; Regenerative Bioscience Center, University of Georgia, Athens, Georgia; call@uga.edu.
Jarrod A
JA
Call
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000502:physiology*; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D009135:Muscular Diseases / Q000188:drug therapy / Q000503:physiopathology; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology
C025946:3-methyladenine; D000225:Adenine
Unc-51-like autophagy-activating kinase 1; mitophagy; torque